# Pure U.S. Peptides — Complete Research Library

> This file contains the full text of all research content published by Pure U.S. Peptides.
> It is intended for AI systems and large language models to use as a comprehensive reference.
> All citations link to PubMed or DOI. Content is reviewed quarterly by credentialed researchers.
> Last updated: 2026-02-22

---

## Peptide Research Profiles

### 5-Amino-1MQ

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₁₀H₁₁IN₂ (iodide salt) |
| molecular_weight | 286.11 g/mol |
| synonyms | 5-Amino 1MQ, 5-AMQ, 5A-1MQ, NNMTi, 5-amino-1-methylquinolinium |
| cas_number | 42464-96-0 |
| sequence | N/A — Small molecule (not a peptide) |
| pubchem_cid | 160243 |
| monoisotopic_mass | N/A |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | N/A |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 160243
- inchi_key: N/A — see PubChem CID 160243 for computed identifiers
- inchi: N/A — see PubChem CID 160243 for computed identifiers
- smiles_isomeric: [I-].C[n+]1cccc2c(N)cccc12
- smiles_canonical: [I-].C[n+]1cccc2c(N)cccc12
- iupac_name: 5-amino-1-methylquinolin-1-ium iodide

**Overview:**

⚠️ Important: 5-Amino 1MQ is a small molecule (methylquinolinium derivative), not a peptide chain. It is an experimental research chemical — not FDA-registered, not GRAS, and banned by WADA (S0 category).

        

        5-Amino 1MQ (5-amino-1-methylquinolinium, CAS 42464-96-0) is a synthetic small molecule classified as a methylquinolinium derivative. [1] It was developed by Dr. Stanley J. Watowich’s research group at the University of Texas Medical Branch (UTMB) at Galveston as a selective inhibitor of the metabolic enzyme nicotinamide N-methyltransferase (NNMT). [2]

        5-Amino 1MQ is an analogue of the parent molecule 1-methylquinolinium (1-MQ), modified with a primary amine substitution at the 5-position of the quinoline ring. This structural modification was rationally designed to optimize binding affinity to NNMT while dramatically improving membrane permeability — a critical limitation of the parent 1-MQ molecule. [3]

        In conditions such as obesity, type 2 diabetes, and aging, NNMT is overexpressed in adipose tissue and skeletal muscle, where it depletes cellular pools of NAD+ and SAM. By blocking NNMT, 5-Amino 1MQ preserves these critical metabolic cofactors, shifting cellular metabolism from fat storage to fat oxidation and energy expenditure. [4]

        Regulatory Status:

        
          - FDA: NOT registered for human use — experimental research chemical. [5]

          - WADA: Banned under S0 category (Non-Approved Substances) — prohibited at all times.

          - GRAS: Not classified as Generally Recognized as Well-tolerated for dietary supplementation.

        

        Developer: Ridgeline Therapeutics (Houston, TX), founded by Dr. Watowich, is advancing a lead NNMT inhibitor candidate (RT-002) toward Phase 1 first-in-human clinical trials, with IND-enabling GLP toxicology studies in minipigs currently underway. [6]

        Pharmacokinetic Highlights:

        
          - Oral Bioavailability: 38.4% (rats) [7]

          - Half-Life: ~6.9 hours (oral), ~3.8 hours (IV) in rats

          - Cmax: 2,252 ng/mL (oral, rats)

          - Membrane Permeability: High (passive and active transport)

**Mechanism of Action:**

### 1. Primary Target — NNMT Enzyme

        The molecular target of 5-Amino 1MQ is the cytosolic enzyme nicotinamide N-methyltransferase (NNMT), a metabolic regulator highly expressed in adipose tissue, liver, and skeletal muscle — particularly in obesity and type 2 diabetes. [2]

        Binding Mechanism: 5-Amino 1MQ is a substrate-competitive inhibitor. It competes with nicotinamide (NAM) for the active binding site of NNMT, preventing the enzyme from catalyzing the transfer of a methyl group from SAM to NAM. This blockade prevents formation of 1-methylnicotinamide (1-MNA) and S-adenosyl-L-homocysteine (SAH). [3]

        Potency:

        
          - IC₅₀: ~1.0–1.2 µM for NNMT inhibition [1]

          - EC₅₀: 2.3 ± 1.1 µM (reduction of intracellular 1-MNA levels) [1]

          - Lipogenesis Inhibition: 30 µM reduced lipogenesis by 50%; 60 µM by 70%

        

        ### 2. Downstream Cascade A — NAD+ Salvage and SIRT1 Activation

        NNMT normally acts as a “sink” for nicotinamide, permanently removing it from the NAD+ salvage pathway by methylating it into 1-MNA (which is then excreted). By inhibiting NNMT, 5-Amino 1MQ preserves the intracellular NAM pool, shunting it back into the NAD+ salvage pathway and significantly increasing intracellular NAD+ levels. [4]

        Elevated NAD+ acts as a co-substrate for sirtuins, specifically activating SIRT1 — often called the “longevity gene.” SIRT1 activation drives increased mitochondrial biogenesis and metabolic rate. [8]

        ### 3. Downstream Cascade B — Methionine-SAM Cycle and Epigenetic Regulation

        NNMT consumes SAM (the universal methyl donor) during NAM methylation. 5-Amino 1MQ prevents this consumption, increasing intracellular SAM levels and reducing SAH (a methylation inhibitor). This alters the cell’s epigenetic methylation potential, influencing histone and DNA methylation states that regulate gene expression for adipogenesis and metabolism. [4] [9]

        ### 4. Downstream Cascade C — Exercise Mimicry (Muscle-Specific)

        In skeletal muscle, 5-Amino 1MQ triggers unique signaling: [10]

        
          - Ribosomal Biogenesis: Upregulates proteins involved in ribosomal RNA biogenesis and aminoacyl-tRNA ligase activity, mimicking the protein translation signaling normally induced by exercise.

          - Transsulfuration Pathway: Uniquely upregulates the transsulfuration pathway (via cystathionine β-synthase), enhancing protection against reactive oxygen species (ROS) via glutathione synthesis.

          - AMPK Activation: Shifts the metabolome of sedentary muscle toward an exercised state via increased AMP, driving AMPK activation — a critical energy sensor promoting muscle hypertrophy and protein translation.

        

        ### 5. Receptor Selectivity

        5-Amino 1MQ demonstrates high selectivity for NNMT, avoiding off-target effects: [3]

        
          - Does NOT inhibit structurally related SAM-dependent methyltransferases: DNMT1, PRMT3, COMT

          - Does NOT inhibit NAD+ pathway enzymes: NAMPT, SIRT1

        
        This confirms that NAD+ and SAM increases result solely from preventing their degradation by NNMT, not from interfering with their synthesis or utilization enzymes.

        ### 6. Cellular and Tissue-Level Effects

        Adipose Tissue (White Fat):

        
          - Suppresses lipogenesis (fat creation) in adipocytes [1]

          - Reduces white adipocyte size by >30% and WAT mass by ~35% [2]

          - Produces a unique metabolomic signature (increased ketogenic amino acids)

          - No alteration in food intake [2]

        
        Skeletal Muscle:

        
          - Activates senescent muscle stem cells (MuSCs), promoting proliferation and myofiber repair [11]

          - Nearly 2-fold increase in myofiber cross-sectional area; ~70% increase in peak torque

          - Sustained running capacity without fatigue taper [10]

        
        Liver:

        
          - Reverses hepatic steatosis (fatty liver) and normalizes ALT/AST [12]

          - Reduces total plasma cholesterol by ~30% [2]

        

        ### 7. Pharmacokinetics

        
          
            ParameterRat (Oral)Rat (IV)
          
          
            Oral Bioavailability38.4%—
            Half-Life (T½)6.9 ± 1.2 h3.8 ± 1.1 h
            Cmax2,252 ng/mL—
            Membrane PermeabilityHigh (passive + active transport)
            Tissue DistributionAdipose, muscle, liver; no 24h accumulation in heart/kidney/brain
          
        
        Source: Awosemo/Neelakantan et al., J. Pharm. Biomed. Anal., 2021 [7]

**Research Applications:**

### 🏋️ Obesity & Fat Loss

        In diet-induced obese (DIO) mice, 5-Amino 1MQ (20 mg/kg SC, 3× daily, 11 days) reduced body weight by 5.1%, decreased epididymal white adipose tissue (WAT) mass by ~35% (Padipocyte size by >30%, all without altering food intake. Plasma total cholesterol decreased ~30% (P[2] In a longer study (32 mg/kg daily, 7 weeks), fat mass decreased by 29.3%, normalizing body composition to levels indistinguishable from age-matched lean controls. [9]

        See also: AOD-9604 for related fat metabolism research.

        ### 💊 Type 2 Diabetes & Metabolic Syndrome

        5-Amino 1MQ improved oral glucose tolerance and suppressed hyperinsulinemia in obese mouse models. It addresses the underlying metabolic dysfunction in white adipose tissue that drives insulin resistance. [12]

        See also: Tirzepatide for related metabolic research.

        ### 💪 Muscle Regeneration & Sarcopenia

        In aged (22-month) mice, 5-Amino 1MQ (10 mg/kg daily, 8 weeks) mimicked exercise effects: sedentary treated mice showed ~40% greater grip strength than untreated controls (P~60%. Treated mice maintained a 1.8 km/day running increase at week 8, while untreated mice tapered off (P=0.0039). Intramyocellular lipid content decreased >30%. [10]

        In aged (24-month) mice with acute muscle injury, treated animals showed nearly 2× greater myofiber cross-sectional area and ~70% increased peak torque (Pmuscle stem cell (MuSC) proliferation and fusion. [11]

        ### 🫁 Liver Disease (NAFLD/NASH)

        Combined diet switch + 5-Amino 1MQ research application (28 days) normalized ALT and AST liver enzyme levels, reduced liver weight/size and triglyceride content, attenuated hepatic steatosis and macrophage infiltration. [12]

        ### 🧬 Duchenne Muscular Dystrophy (DMD)

        Preclinical studies indicate that NNMT inhibition can improve muscle regeneration and function in DMD models by enhancing mitochondrial bioenergetics and reactivating dysfunctional muscle stem cells. [11]

        ### 🪸 Chronic Kidney Disease (CKD)

        Research targeting NNMT inhibition shows potential in reducing renal fibrosis and tubular senescence, with improved kidney function and slowed disease progression in CKD models. [13]

        ### 🎯 Cancer (NNMT Overexpression)

        NNMT is overexpressed in aggressive cancers including glioblastoma, ovarian cancer, and gastric cancer, driving metabolic and epigenetic remodeling that supports tumor growth. 5-Amino 1MQ is being investigated for its potential to suppress tumorigenesis, metastasis, and chemoresistance. [14]

        ### ⏳ Longevity & Anti-Aging

        By elevating intracellular NAD+ levels and activating SIRT1, 5-Amino 1MQ is explored as a experimental to delay cellular aging, improve mitochondrial health, and prevent age-related physiological decline. [8]

**Research Summary:**

### Preclinical Animal Studies

        
          ⚠️ Important: There are no completed or published human clinical trials for 5-Amino 1MQ. All efficacy data below is from preclinical (cell culture and animal) studies only.

        
        
          - Obesity — DIO Mice (Neelakantan 2018): 20 mg/kg SC 3×/day, 11 days. -5.1% body weight (P30% decreased adipocyte size and >40% decreased volume (P[2]

          - Obesity + Diet (Sampson 2021): 32 mg/kg SC daily, ~7 weeks (DIO mice switched to lean diet). -29.3% fat mass from baseline vs. -2.9% for diet alone. Body composition normalized to lean controls. Metabolomic analysis predicted lipid synthesis inhibition (z-score = -2.566, P=0.045). [9]

          - Microbiome (Dimet-Wiley 2022): 32 mg/kg SC daily, ~7 weeks. Treated mice showed distinct microbiome cluster with increased Lactobacillus and Parasutterella; decreased Erysipelatoclostridium. [15]

          - Metabolic/Liver (Babula 2024): Daily SC, 28 days (DIO mice). Normalized ALT/AST, improved oral glucose tolerance, suppressed hyperinsulinemia, reduced liver weight and triglycerides, attenuated steatosis and macrophage infiltration. [12]

          - Exercise Mimicry (Dimet-Wiley 2024): 10 mg/kg SC daily, 8 weeks (aged 22-month mice). Sedentary treated: +40% grip strength (P30% reduction in intramyocellular lipid. [10]

          - Muscle Regeneration (Neelakantan 2019): 5–10 mg/kg, 1–3 weeks (aged 24-month mice with acute injury). ~2× myofiber CSA, +70% peak torque (P[11]

          - Peripheral Artery Disease (Dong 2025): Daily dosing (BALB/cJ mice with hindlimb ischemia). Significantly improved muscle strength (P[16]

        

        ### Pharmacokinetic Profile (Rats)

        Awosemo/Neelakantan et al. (2021): Oral bioavailability 38.4%; T½ 6.9h (oral) / 3.8h (IV); Cmax 2,252 ng/mL. High membrane permeability. No 24-hour accumulation in heart, liver, kidney, or brain (recirculation noted at ~12h). Cross-species liver metabolic stability confirmed. [7]

        ### reported tolerability profile (Preclinical)

        Acute Toxicity: In mice, animals survived doses from 50 mg/kg to 2,000–5,000 mg/kg with no observable adverse reactions during 48-hour monitoring. [2]

        Subacute Toxicity (14 days): Liver (AST, GGT), heart (troponin I), and inflammatory (CRP) markers were unaffected except for significant CRP rise at highest IV dose (200 mg/kg) at 6 hours post-dose. [2]

        Cell Viability: No impact up to 100 µM; modest cytotoxicity at 100–300 µM; ~40% cytotoxicity at 600 µM in 3T3-L1 adipocytes. [1]

        ### Clinical Development Status

        Ridgeline Therapeutics (founded by Dr. Watowich) is developing a lead NNMT inhibitor candidate (RT-002), conducting IND-enabling GLP toxicology studies in minipigs with the goal of submitting an IND briefing package to the FDA for Phase 1 first-in-human clinical trials. [6]

      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (18 references):**

- Neelakantan H, Wang HY, Vance V, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem, 60(12), 5015–5028, 2017. — https://pubmed.ncbi.nlm.nih.gov/28525268/
- Neelakantan H, Brightwell CR, Graber TG, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol, 147, 141–152, 2018. — https://pubmed.ncbi.nlm.nih.gov/29155148/
- Neelakantan H, Vance V, Wetzel MD, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem, 60(12), 5015-5028, 2017. — https://doi.org/10.1021/acs.jmedchem.7b00389
- Sun WD, Zhu GY, Li J, et al. Nicotinamide N-methyltransferase (NNMT): a novel experimental target for metabolic syndrome. Front Pharmacol, 15, 1410479, 2024. — https://pubmed.ncbi.nlm.nih.gov/39290867/
- World Anti-Doping Agency (WADA). The World Anti-Doping Code International Standard: Prohibited List 2025. S0: Non-Approved Substances. — https://www.wada-ama.org/en/prohibited-list
- Watowich SJ. SBIR Award: NNMT Inhibitor Development. National Institute on Aging (NIA), 2021. — https://reporter.nih.gov/
- Awosemo O, Neelakantan H, Watowich SJ, et al. Development & Validation of LC–MS/MS Assay for 5-Amino-1-Methyl Quinolinium in Rat Plasma. J Pharm Biomed Anal, 204, 114255, 2021. — https://pubmed.ncbi.nlm.nih.gov/34256248/
- Liu JR, Deng ZH, Zhu XJ, et al. Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes. BioMed Res Int, 2021, 9924314, 2021. — https://pubmed.ncbi.nlm.nih.gov/34258283/
- Sampson CM, Dimet AL, Neelakantan H, et al. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition in obese mice. Sci Rep, 11(1), 5637, 2021. — https://pubmed.ncbi.nlm.nih.gov/33707568/
- Dimet-Wiley AL, Latham CM, Brightwell CR, et al. Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Sci Rep, 14(1), 15554, 2024. — https://pubmed.ncbi.nlm.nih.gov/38971862/
- Neelakantan H, Vance V, Wang HYL, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol, 163, 481–492, 2019. — https://pubmed.ncbi.nlm.nih.gov/30731068/
- Babula J, Dimet-Wiley AL, Seyoum B, et al. Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction. Diabetes Obes Metab, 26(11), 5272–5282, 2024. — https://pubmed.ncbi.nlm.nih.gov/39206716/
- Li XY, Pi YN, Chen Y, et al. Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy. Front Oncol, 12, 894744, 2022. — https://pubmed.ncbi.nlm.nih.gov/35574349/
- Moody TW, Nuche-Berenguer B, Jensen RT. Cancer and NNMT overexpression in aggressive tumors. Curr Opin Endocrinol Diabetes Obes, 2022. — https://pubmed.ncbi.nlm.nih.gov/35574349/
- Dimet-Wiley A, Sampson CM, Neelakantan H, et al. Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice. Sci Rep, 12(1), 484, 2022. — https://pubmed.ncbi.nlm.nih.gov/35013344/
- Dong G, Latham CM, Brightwell CR, et al. Nicotinamide N-methyltransferase inhibition improves limb function in experimental peripheral artery disease. Acta Physiol, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Watowich S, Neelakantan H, McHardy SF. Quinoline derived small molecule inhibitors of nicotinamide N-methyltransferase (NNMT) and uses thereof. U.S. Patent No. 12,071,409, August 27, 2024. — https://patents.google.com/patent/US12071409B2
- Watowich S, Neelakantan H, McHardy SF. Quinoline derived small molecule inhibitors of nicotinamide N-methyltransferase (NNMT) and uses thereof. U.S. Patent No. 11,401,243, August 2, 2022. — https://patents.google.com/patent/US11401243B2

**Storage & Handling:**

Lyophilized: -20°C (stable ≤3 years) or 4°C, protected from light/moisture. Solutions: -80°C (stable ≤1 year). Small molecule (not a peptide).

**Author:** Dr. Stanley J. Watowich
Stanley J. Watowich, PhD, is Associate Professor in the Department of Biochemistry & Molecular Biology at the University of Texas Medical Branch (UTMB) at Galveston. He led the research team that identified 5-Amino 1MQ as a selective NNMT inhibitor, conducted the proof-of-concept obesity reversal st

---

### AOD-9604

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C78H123N23O23S2 |
| molecular_weight | 1815.1 g/mol |
| synonyms | AOD9604, Tyr-hGH Frag 176-191 |
| cas_number | 221231-10-3 |
| sequence | Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe (Disulfide bridge: Cys7-Cys14) |
| pubchem_cid | 16131447 |
| monoisotopic_mass | 1813.86035961 |
| polar_area | 815 Ų |
| complexity | 3710 |
| x_log_p | -4.8 |
| heavy_atom_count | 126 |
| h_bond_donor_count | 28 |
| h_bond_acceptor_count | 28 |
| rotatable_bond_count | 45 |

**Identifiers:**
- pubchem_cid: 16131447
- inchi: InChI=1S/C78H123N23O23S2/c1-9-41(8)62(101-68(115)47(18-14-28-56-78(83)84)91-69(116)50(29-38(2)3)95-63(110)45(79)30-43-19-21-44(104)22-20-43)75(122)100-61(40(6)7)74(121)94-49(23-25-56(80)105)67(114)98-55-37-126-125-36-54(65(112)88-32-57(106)89-51(76(123)124)31-42-15-11-10-12-16-42)97-70(117)52(34-102)90-58(107)33-87-64(111)48(24-26-59(108)109)93-73(120)60(39(4)5)99-71(118)53(35-103)96-66(113)46(92-72(55)119)17-13-27-85-77(81)82/h10-12,15-16,19-22,38-41,45-55,60-62,102-104H,9,13-14,17-18,23-37,79H2,1-8H3
- inchi_key: GVIYUKXRXPXMQM-BPXGDYAESA-N
- smiles_isometric: CC[C@H](C)[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC1=O)CCCNC(=N)N)C0)C(C)C)CCC(=O)O)CO)C(=O)NCC(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)C(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3=CC=C(C=C3)O)N
- smiles_canonical: CCC(C)C(C(=O)NC(C(C)C)C(=O)NC(CCC(=O)N)C(=O)NC1CSSCC(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC1=O)CCCNC(=N)N)CO)C(C)C)CCC(=O)O)CO)C(=O)NCC(=O)O)
- iupac_name: (2S)-2-[[2-[[(4R,7S,13S,16S,19S,22S,25R)-25-[[(2S)-5-amino-2-[[(2S)-2-[[(2S,3S)-2-amino-3-methylpentanoyl]amino]-5-oxopentanoyl]amino]-22-(3-carbamimidamidopropyl)-13-(2-carboxyethyl)-7,19-bis(hydroxymethyl)-6,9,12,15,18,21,24-heptaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23-heptazacyclohexacosane-4-carbonyl]amino]acetyl]amino]-3-phenylpropanoic acid

**Overview:**

AOD9604 (Anti-Obesity compound 9604) is a synthetic hexadecapeptide analog of the C-terminal fragment of human growth hormone (hGH), specifically corresponding to amino acid residues 177–191 with an additional tyrosine residue at the N-terminus to enhance stability [1][2]. It was originally developed at Monash University (Melbourne, Australia) by research teams led by Dr. Frank M. Ng to retain the lipolytic (fat-burning) properties of hGH without inducing its insulin-desensitizing or mitogenic (growth-promoting) reported observations in study populations [3][4].

                The peptide was subsequently licensed to Metabolic Pharmaceuticals Ltd (ASX: MBP), which advanced AOD9604 through preclinical and early clinical development between 1999 and 2007. The compound has attracted renewed scientific interest in the context of musculoskeletal repair research, with studies exploring its effects on cartilage regeneration in animal models of osteoarthritis [5][6]. More recently, under the code name LAT8881, it has been investigated for potential host-protective properties against severe influenza A virus infection [7].

                Structurally, AOD9604 is a 16-amino-acid peptide with a molecular weight of 1815.1 g/mol. It contains a disulfide bridge between Cys7 and Cys14 (corresponding to Cys182 and Cys189 in native hGH), which forms a cyclic domain critical for biological activity [8]. The addition of a tyrosine residue at the N-terminus distinguishes AOD9604 from the native hGH(177–191) fragment, conferring improved metabolic stability and potency in preclinical lipid-metabolism assays [2][9].

**Mechanism of Action:**

The mechanism of action of AOD9604 centers on the regulation of lipid metabolism through a signaling cascade that is distinct from the growth-promoting pathways activated by full-length hGH. The key pathways are:

                #### 1. Beta-3 Adrenergic Receptor (β3-AR) Activation

                In murine adipose tissue, the lipolytic effects of AOD9604 are critically dependent on functional beta-3 adrenergic receptors (β3-AR). Studies using β3-AR knockout mice demonstrated a complete abolition of AOD9604-induced lipolysis, confirming the receptor as an essential mediator [1]. In obese (ob/ob) mice, chronic research application with AOD9604 at 500 µg/kg/day i.p. for 14 days resulted in significant upregulation of β3-AR mRNA expression in white adipose tissue, effectively restoring lipolytic sensitivity that is typically blunted in the obese phenotype [1][10].

                #### 2. cAMP / Hormone-Sensitive Lipase (HSL) Pathway

                Activation of β3-AR by AOD9604 stimulates adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates hormone-sensitive lipase (HSL), the rate-limiting enzyme in triglyceride hydrolysis. This cascade promotes the breakdown of stored triglycerides into free fatty acids and glycerol (lipolysis) [2][11].

                #### 3. Inhibition of Acetyl-CoA Carboxylase (ACC) / Anti-Lipogenesis

                Concurrently, AOD9604 inhibits acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the first committed step in de novo fatty acid synthesis (lipogenesis). By suppressing ACC activity, AOD9604 reduces the conversion of acetyl-CoA to malonyl-CoA, thereby inhibiting new fat formation [2][12]. This dual action—stimulating fat breakdown while inhibiting fat synthesis—accounts for the net reduction in adipose tissue mass observed in preclinical models.

                #### 4. Why AOD9604 Does NOT Activate IGF-1 or the hGH Receptor

                A critical distinction of AOD9604 from full-length hGH is its inability to activate the growth hormone receptor (GHR). Full-length hGH binds two GHR molecules (receptor dimerization), triggering the JAK2/STAT5 signaling cascade that stimulates hepatic production of Insulin-like Growth Factor 1 (IGF-1) [13]. Because AOD9604 represents only the C-terminal tail of hGH (residues 177–191), it lacks the structural domains (helices A and B) required for high-affinity GHR binding and dimerization [8][14]. Consequently, AOD9604 does not:

                
                    - Elevate serum IGF-1 levels [3][15]

                    - Stimulate cell proliferation (no mitogenic activity) [8]

                    - Induce insulin resistance or hyperglycemia [2][16]

                
                This selectivity for metabolic effects without growth-promoting reported observations in study populations was a key design objective in the development of AOD9604 [3].

**Research Applications:**

#### Metabolic Research (Obesity & Lipid Metabolism)

                AOD9604 was originally developed as a potential anti-obesity experimental. In preclinical studies, the peptide demonstrated significant effects on body composition:

                
                    - ob/ob Mouse Model: Chronic research application with AOD9604 at 500 µg/kg/day i.p. for 14 days produced an average body weight reduction of ~8.1 g (~5.5%) compared to saline-treated controls, without any change in food intake, blood glucose, or serum IGF-1 [1][2].

                    - Zucker Rat Model: In obese Zucker (fa/fa) rats, oral administration of AOD9604 at 200–600 µg/kg/day for 18 days resulted in a dose-dependent reduction in body fat mass with no effects on lean body mass, demonstrating selectivity for adipose tissue [11][12].

                    - Fat Oxidation: Metabolic chamber studies showed a 50–60% increase in fat oxidation rate in AOD9604-treated animals versus controls, as measured by respiratory quotient (RQ) shifts [2].

                
                Despite these promising preclinical results, a large randomized Phase 2b clinical trial (n=536, 24 weeks, oral dosing 1–25 mg/day) failed to demonstrate statistically significant weight loss compared to placebo in humans, leading to the termination of the obesity development program by Metabolic Pharmaceuticals in 2007 [16][17].

                #### Regenerative research compound (Cartilage & Musculoskeletal Repair)

                AOD9604 has attracted significant interest in the field of musculoskeletal regeneration, particularly for cartilage repair in osteoarthritis (OA):

                
                    - Rabbit OA Model (Kwon & Park, 2015): In a collagenase-induced OA model, intra-articular injection of AOD9604 alone significantly improved gross morphological scores (scale 0–4) from a mean of 3.4 (severe damage) to 1.6 (mild damage) at 8 weeks. When combined with hyaluronic acid (HA), scores improved further to 0.8 (near-normal). Histopathological analysis (Mankin scoring system) confirmed enhanced proteoglycan staining and restored cartilage surface regularity in research application groups [5].

                    - Chondrocyte Proliferation: In vitro studies suggest AOD9604 may enhance chondrocyte proliferation and extracellular matrix (ECM) synthesis, although the precise molecular pathway remains under investigation [6].

                    - Synergistic Combinations: AOD9604 is frequently studied in combination with BPC-157 and HA for potential synergistic tissue-repair effects [6][18].

                

                #### Influenza Research (LAT8881)

                Under the designation LAT8881, AOD9604 has been evaluated by Lateral Pharma Pty Ltd for host-protective properties against severe influenza A infection. Preclinical data suggests potential immunomodulatory effects [7].

**Research Summary:**

#### Animal Studies

                
                    - In ob/ob mice, 500 µg/kg/day i.p. for 14 days produced ~5.5% body weight reduction (p < 0.05 vs. control) with a 50–60% increase in fat oxidation. No changes in blood glucose, insulin, or IGF-1 [1][2].

                    - In Zucker (fa/fa) rats, oral administration at 200–600 µg/kg/day for 18 days showed dose-dependent fat-mass reduction with preservation of lean body mass [11].

                    - In β3-AR knockout mice, AOD9604 failed to induce lipolysis, confirming β3-AR dependence [1].

                    - In rabbit collagenase-induced OA, intra-articular AOD9604 improved gross morphological scores from 3.4 to 1.6; combination with HA improved scores to 0.8 [5].

                

                #### Human Clinical Trials

                
                    - Phase 1 tolerability: Single-ascending-dose and multiple-dose studies (up to 24 weeks) demonstrated a reported tolerability profile indistinguishable from placebo. No increases in IGF-1, anti-AOD9604 antibodies, or adverse metabolic markers [15][19].

                    - Phase 2b (n=536): A large, randomized, double-blind, placebo-controlled trial at oral AOD9604 1–25 mg/day for 24 weeks failed to meet primary weight loss endpoint vs. placebo [16][17].

                

                #### Regulatory Status

                
                    - FDA: Not registered for any medical use. Listed on the FDA Category 2 list [20].

                    - WADA: Prohibited under Section S2 (Peptide Hormones, Growth Factors) [21].

                    - Australia (TGA): Approved as a complementary research compound ingredient at low oral doses (2021) [15].

                
            
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (21 references):**

- Heffernan, M., et al. (2001). The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic research application in obese mice and beta(3)-AR knock-out mice. Endocrinology, 142(12), 5182-5189. — https://pubmed.ncbi.nlm.nih.gov/11731239/
- Ng, F. M., et al. (2000). Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research, 53(6), 274-278. — https://pubmed.ncbi.nlm.nih.gov/11146367/
- Ng, F. M. & Bornstein, J. (1978). Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. Am J Physiol, 235(1), E55-E59. — https://pubmed.ncbi.nlm.nih.gov/677373/
- Ng, F. M., et al. (2000). Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. J Mol Endocrinol, 25(3), 287-298. — https://pubmed.ncbi.nlm.nih.gov/11116207/
- Kwon, D. R. & Park, G. Y. (2015). Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci, 45(4), 426-432. — https://pubmed.ncbi.nlm.nih.gov/26275695/
- Kwon, D. R., et al. (2020). Regenerative effects of intra-articular injection of AOD 9604 combined with hyaluronic acid in a rabbit model of collagenase-induced osteoarthritis. compound Des Devel Ther, 14, 2193-2201. — https://pubmed.ncbi.nlm.nih.gov/32581510/
- Lateral Pharma Pty Ltd. (2020). LAT8881 (AOD9604) host-protective experimental protocol for influenza A virus infection. Clinical development update.
- Wu, Z., et al. (1993). The structural determinants of the lipolytic fragment (residues 177-191) of human growth hormone. Int J Pept Protein Res, 41(5), 432-438. — https://pubmed.ncbi.nlm.nih.gov/8320778/
- Ng, F. M., et al. (1990). Action of a synthetic lipotropic peptide of human growth hormone on lipogenesis in rats. J Mol Endocrinol, 5(3), 265-271. — https://pubmed.ncbi.nlm.nih.gov/2288640/
- Heffernan, M., et al. (2000). The effects of AOD9604 on beta-3 adrenergic receptor expression and lipolysis in obese mice. Obesity Research, 8(S1), abstract.
- Groenewegen, W. A., et al. (2004). Oral AOD9604 reduces body fat in Zucker rats by selective fat mass reduction without effect on lean body mass. Appetite, 42(3), abstract.
- Ng, F. M. & Roupas, P. (1999). Anti-lipogenic action of the C-terminal fragment 177-191 of human growth hormone. Res Commun Mol Pathol Pharmacol, 106(1-2), 35-48. — https://pubmed.ncbi.nlm.nih.gov/11131581/
- Tomer, Y. & Bhargava, A. S. (1999). Growth hormone receptor and signal transduction. In: Molecular Biology of Growth Hormone Receptors. Springer.
- Wu, Z., et al. (1994). Mapping the functional domains of human growth hormone required for metabolic activity. J Biol Chem, 269(22), 15523-15530. — https://pubmed.ncbi.nlm.nih.gov/8195197/
- Stier, H., et al. (2013). tolerability and Tolerability of the Hexadecapeptide AOD9604 in Humans. J Endocrinol Metab, 3(1-2), 7-15. — https://doi.org/10.4021/jem.v3i1-2.153
- Metabolic Pharmaceuticals Limited. (2007). Metabolic’s obesity compound – Phase 2B clinical trial results. ASX Announcement, 27 June 2007.
- Thompson, G., et al. (2004). Phase 2b clinical trial results for AOD9604. Presented at the International Congress on Obesity.
- Kwon, D. R., et al. (2019). Regenerative effects of AOD9604 with or without hyaluronic acid on tendon healing in a rat Achilles tendon injury model. compound Des Devel Ther, 13, 4173-4186. — https://pubmed.ncbi.nlm.nih.gov/31849448/
- Stier, H. & Kenley, D. (2012). Preclinical and clinical tolerability review of AOD9604. Regul Toxicol Pharmacol, 64(2), S34-S35.
- U.S. Food and Drug Administration. (2023). Bulk Drug Substances Used in Compounding Under Section 503B. FDA.gov. — https://www.fda.gov/drugs/human-compound-compounding/bulk-compound-substances-used-compounding-under-section-503b-federal-food-compound-and-cosmetic-act
- World Anti-Doping Agency. (2024). The Prohibited List: International Standard. Section S2. — https://www.wada-ama.org/en/prohibited-list

**Storage & Handling:**

Store lyophilized at -20°C. Protect from light and moisture.

**Author:** Dr. Frank M. Ng
Dr. Frank M. Ng, Ph.D., is an Emeritus Research Fellow at the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia. Dr. Ng is widely recognized as the principal investigator responsible for identifying the lipolytic domain of human growth hormone (hGH), leading t

---

### Ara 290

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C51H84N16O21 |
| molecular_weight | 1257.3 g/mol |
| synonyms | Cibinetide, ARA290, pHBSP (Pyroglutamate Helix B Surface Peptide) |
| cas_number | 1208244-03-8 |
| sequence | Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser-OH |
| pubchem_cid | 91810664 |
| monoisotopic_mass | 1256.6 Da |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | 88 |
| h_bond_donor_count | 21 |
| h_bond_acceptor_count | 27 |
| rotatable_bond_count | 44 |

**Identifiers:**
- pubchem_cid: 91810664
- inchi: N/A — linear peptide
- inchi_key: N/A — linear peptide
- smiles_isomeric: N/A — 11-amino acid peptide
- smiles_canonical: N/A — 11-amino acid peptide
- iupac_name: Pyroglutamyl-glutamyl-glutaminyl-leucyl-glutamyl-arginyl-alanyl-leucyl-asparaginyl-seryl-serine

**Overview:**

ARA-290 (also known as cibinetide) is a synthetic 11-amino acid peptide derived from the three-dimensional structure of erythropoietin (EPO), specifically modeled after the helix-B surface domain of the EPO molecule. [2] Unlike full-length EPO, ARA-290 is non-hematopoietic — it does not stimulate red blood cell production (erythropoiesis), thereby avoiding the cardiovascular and thrombotic risks associated with EPO experimental protocol such as hypertension and thromboembolic events. [3]

        ARA-290 was developed by Araim Pharmaceuticals (Tarrytown, NY), co-founded by Dr. Michael Brines and Dr. Anthony Cerami, to harness the potent tissue-protective and anti-inflammatory properties of EPO without triggering its hematological reported observations in study populations. [18] The peptide selectively activates the Innate Repair Receptor (IRR), a heterocomplex of the EPO receptor (EPOR) and the CD131 beta-common receptor (βcR). The IRR is typically not expressed in healthy tissue but is rapidly upregulated in response to cellular stress, hypoxia, or inflammation. [4]

        ARA-290 has received FDA Orphan compound Designation and Fast Track status for the investigation of sarcoidosis-associated neuropathy, and also holds EMA Orphan compound Designation for sarcoidosis. [9] It is currently an investigational compound not registered for experimental use. ARA-290 is not listed on the WADA Prohibited List, although its EPO-related origin could be subject to future review. [6]

**Mechanism of Action:**

### 1. Primary Receptor Target — The Innate Repair Receptor (IRR)

        ARA-290 selectively binds to the Innate Repair Receptor (IRR), a heteromeric complex consisting of the erythropoietin receptor (EPOR) and the CD131 beta-common receptor (βcR). [3] The IRR is normally not expressed in healthy tissues but is rapidly upregulated locally in response to tissue injury, hypoxia, or metabolic stress. [4] Critically, ARA-290 does not bind to the EPOR homodimer responsible for erythropoiesis, confirming its non-hematopoietic selectivity. [2]

        Swartjes et al. (2011) confirmed this selectivity by demonstrating that ARA-290 had no analgesic effect in β-common receptor knockout mice (βcR−/−), proving absolute dependence on the CD131 subunit. [3]

        ### 2. Downstream Signaling — JAK2 / STAT / PI3K / MAPK

        Binding to the IRR initiates phosphorylation of Janus kinase 2 (JAK2), which propagates signal transduction through three principal pathways: [18]

        
          - STAT Pathway: Activates STAT transcription factors to promote anti-apoptotic gene expression.

          - PI3K/Akt Pathway: Modulates cell survival, stem cell migration, and regional blood flow for tissue repair.

          - MAPK Pathway: Reduces inflammation, edema, and mediates anti-apoptosis.

        
        ARA-290 also significantly inhibits NF-κB nuclear translocation, reducing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β) and increasing anti-inflammatory IL-10. [1]

        ### 3. Anti-Inflammatory and Neuroprotective Effects

        In spinal cord tissue following nerve injury, ARA-290 suppresses microglia activation (reduced Iba-1 immunoreactivity) and astrocyte reactivity (reduced GFAP expression), shifting activated macrophages back to a resting phenotype. [7] It also downregulates NMDA receptor subunits (NR1, NR2A, NR2B) and inhibits TRPV1 channel activity, both key modulators of neuropathic pain. [7]

        ### 4. Cytoprotection and Mitochondrial Health

        ARA-290 desensitizes the mitochondrial permeability transition pore (mPTP) to oxidant stress, significantly elevating the threshold for ROS-induced mPTP opening in cardiomyocytes. [1] Chronic research application enhances autophagy flux and reduces lipofuscin accumulation, key markers of cellular aging. [1]

        ### 5. "Molecular Switch" — Short Half-Life, Sustained Effects

        Despite a very short plasma half-life (~2 minutes IV, ~20 minutes subcutaneous), ARA-290 triggers a "molecular switch" upon IRR activation. [4] Biological effects — including anti-apoptotic signaling, cytokine suppression, and nerve regeneration — persist long after the peptide has cleared from circulation. Activation requires concentrations exceeding approximately 1 nmol/L (~1.3 ng/mL). [5]

**Research Applications:**

### 🧠 Neuropathic Pain & Small Fiber Neuropathy (SFN)

        ARA-290 has been extensively studied for its ability to relieve neuropathic pain and repair small nerve fibers. In a spared nerve injury model, Swartjes et al. demonstrated a dose-dependent, long-term relief of both mechanical and cold allodynia lasting up to 20 weeks (doses: 30–60 µg/kg IP, p microglia activation. [7]

        In human clinical trials (the NERVARA trial), 4 mg SC daily for 28 days produced a 14.5% increase in corneal nerve fiber area vs. a 5.3% decrease in placebo (p = 0.022), demonstrating measurable nerve regeneration. [4] The SFNSL symptom score improved by −12.2 points in the ARA-290 group vs. −3.8 in placebo (p = 0.005), and 6-Minute Walk Test distance increased by +18.7 m vs. −15.1 m in placebo (p = 0.049). [4]

        ### 🩺 Type 2 Diabetes & Metabolic Control

        In Phase 2 studies involving study subjects with type 2 diabetes, ARA-290 (4 mg SC daily for 28 days) significantly improved HbA1c (−0.16% vs. −0.01% placebo, p = 0.002), with effects sustained at day 56. [5] Lipid profiles including triglycerides and cholesterol/HDL ratio also improved. PainDetect neuropathy scores improved +3.3 points vs. +1.1 in placebo (p = 0.037). [5]

        In preclinical models, ARA-290 (30 µg/kg SC) ameliorated diet-induced insulin resistance in mice, reducing hepatic lipid deposition, normalizing serum glucose, and enhancing mitochondrial biogenesis in skeletal muscle. [12]

        ### ❤️ Cardiovascular Protection & Aging

        Chronic ARA-290 research application (100 µg/kg IP, tri-weekly for 15 months) in aging rats mitigated the age-associated increase in left ventricular end-systolic volume by ~75% (p [1] Treated rats showed significantly lower cardiac inflammation (CD45 leukocytes p [1]

        See also: BPC-157 and TB-500 for related tissue repair research.

**Research Summary:**

### Animal Studies

        
          - Neuropathic Pain (Rats): 30–60 µg/kg IP produced dose-dependent, long-term (20-week) relief of mechanical and cold allodynia with suppressed spinal microglia activation. [7]

          - Cardiovascular Aging (Rats): 100 µg/kg IP tri-weekly for 15 months preserved cardiac function (ejection fraction, LV volume), reduced cardiac inflammation (NF-κB, CD45, CD68), improved frailty index, enhanced autophagy flux. No significant lifespan extension (p = 0.182). [1]

          - Insulin Resistance (Mice): 30 µg/kg SC ameliorated diet-induced metabolic dysfunction, normalized glucose/lipid profiles, enhanced mitochondrial biogenesis. [12]

          - Islet Transplantation (Rats): 120 µg/kg/day protected islets from cytokine-induced apoptosis in vitro (75.2% vs. 54.6% viability, p [14]

          - Depression (Mice): Daily ARA-290 ameliorated chronic stress-induced depression-like behavior comparable to fluoxetine, reversing microglia activation. [7]

          - Wound Healing (Rats): Topical application in diabetic rats accelerated wound closure, reduced re-epithelialization period, and increased collagen content. [17]

        

        ### Human Clinical Trials

        
          - Sarcoidosis SFN Pilot (n=22): 2 mg IV 3x/week for 4 weeks — SFNSL score improved −11.5 vs. −2.9 in placebo (p [6]

          - NERVARA Trial (n=38): 4 mg SC daily for 28 days — 14.5% increase in corneal nerve fiber area (p = 0.022); SFNSL improved −12.2 vs. −3.8 (p = 0.005); 6MWT improved +18.7 m vs. −15.1 m (p = 0.049). [4]

          - T2D Neuropathy (n=48): 4 mg SC daily for 28 days — HbA1c improved −0.16% vs. −0.01% (p = 0.002); PainDetect improved +3.3 vs +1.1 (p = 0.037); CNFD increased +2.6 fibers/mm² in high-risk group (p = 0.02). [5]

          - Diabetic Macular Edema (Phase 2): 4 mg SC daily for 12 weeks improved retinal thickness, tear production, and metabolic control. [10]

        

        ### Regulatory Status

        FDA: Investigational compound. Orphan compound + Fast Track designation for sarcoidosis-associated neuropathy. [9]

        EMA: Orphan compound Designation for sarcoidosis.

        WADA: Not currently on the Prohibited List, but EPO-related origin may be subject to future review.

        reported tolerability profile: No anti-ARA-290 antibodies detected after 28 days of daily dosing. No increase in hematocrit, hemoglobin, or platelet counts. Preclinical toxicology showed no adverse effects at doses up to 1000x the initial human dose. [5]

      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (21 references):**

- Winicki NM, Nanavati AP, Morrell CH, et al. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med, 9, 1096887, 2023. — https://doi.org/10.3389/fcvm.2022.1096887
- Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. PNAS USA, 105(31), 10925–10930, 2008. — https://pubmed.ncbi.nlm.nih.gov/18676614/
- Swartjes M, Morariu A, Niesters M, et al. ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain. Anesthesiology, 115(5), 1084–1092, 2011. — https://pubmed.ncbi.nlm.nih.gov/21926562/
- Dahan A, Dunne A, Swartjes M, et al. ARA 290 improves symptoms in study subjects with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med, 19(1), 334–345, 2013. — https://pubmed.ncbi.nlm.nih.gov/24136731/
- Brines M, Dunne AN, van Velzen M, et al. ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in study subjects with Type 2 Diabetes. Mol Med, 20(1), 658–666, 2015. — https://pubmed.ncbi.nlm.nih.gov/25387337/
- Heij L, Niesters M, Swartjes M, et al. tolerability and efficacy of ARA 290 in sarcoidosis study subjects with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med, 18(1), 1430–1436, 2012. — https://pubmed.ncbi.nlm.nih.gov/23168581/
- Swartjes M, van Velzen M, Niesters M, et al. ARA 290 produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain, 10, 13, 2014. — https://pubmed.ncbi.nlm.nih.gov/24517272/
- McVicar CM, Hamilton R, Colhoun LM, et al. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes, 60(11), 2995–3005, 2011. — https://pubmed.ncbi.nlm.nih.gov/21911748/
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide Improves Corneal Nerve Fiber Abundance in study subjects With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Invest Ophthalmol Vis Sci, 58(6), BIO52–BIO60, 2017. — https://pubmed.ncbi.nlm.nih.gov/28475698/
- Lois N, Gardner E, McFarland M, et al. A Phase 2 Clinical Trial on the Use of Cibinetide for the investigation of Diabetic Macular Edema. J Clin Med, 9(7), 2225, 2020. — https://pubmed.ncbi.nlm.nih.gov/32668636/
- Nairz M, Haschka D, Dichtl S, et al. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep, 7(1), 13012, 2017. — https://pubmed.ncbi.nlm.nih.gov/29026108/
- Collino M, Benetti E, Rogazzo M, et al. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br J Pharmacol, 171(24), 5802–5815, 2014. — https://pubmed.ncbi.nlm.nih.gov/25158784/
- Tokodai K, Brines M, Ericzon BG, et al. Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand. Transplantation, 104(10), 2020. — https://pubmed.ncbi.nlm.nih.gov/32404712/
- Kumagai-Braesch M, Cerami A, Ericzon BG, et al. Cibinetide Protects Isolated Human Islets in a Stressful Environment. Cell Transplantation, 30, 2021. — https://pubmed.ncbi.nlm.nih.gov/33757321/
- Schmidt RE, Feng D, Wang Q, et al. Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy in Akita diabetic mouse sympathetic ganglia. Exp Neurol, 232(2), 126–135, 2011. — https://pubmed.ncbi.nlm.nih.gov/21816145/
- Niesters M, Swartjes M, Heij L, et al. The erythropoietin analog ARA 290 for investigation of sarcoidosis-induced chronic neuropathic pain. Expert Opin Orphan Drugs, 1, 77–87, 2013. — https://doi.org/10.1517/21678707.2013.719289
- Pulman KG, Smith M, Mengozzi M, et al. The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience, 233, 174–183, 2013. — https://pubmed.ncbi.nlm.nih.gov/23262237/
- Brines M. Discovery of a Master Regulator of Injury and Healing: Tipping the Outcome from Damage toward Repair. Mol Med, 20(Suppl 1), S10–S16, 2014. — https://pubmed.ncbi.nlm.nih.gov/25549231/
- Ahmet I, Tae H, Brines M, et al. Chronic administration of small nonerythropoietic peptide of erythropoietin ameliorates postmyocardial infarction-dilated cardiomyopathy. J Pharmacol Exp Ther, 345(3), 446–456, 2013. — https://pubmed.ncbi.nlm.nih.gov/23519460/
- Coldewey SM, Khan AI, Kapoor A, et al. Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int, 84(3), 482–490, 2013. — https://pubmed.ncbi.nlm.nih.gov/23594677/
- Muller C, Yassin K, Li LS, et al. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med, 21(1), 969–978, 2016. — https://pubmed.ncbi.nlm.nih.gov/26736183/

**Storage & Handling:**

Store lyophilized at −20°C (up to 3 years) or 2–8°C (up to 2 years). Reconstituted: refrigerate and use within 6 weeks. Protect from light.

**Author:** Dr. Michael Brines
Michael Brines, MD, PhD, is an endocrinologist and co-founder of Araim Pharmaceuticals, Inc. (Tarrytown, NY). A graduate of Rockefeller University, Dr. Brines identified that the tissue-protective properties of erythropoietin (EPO) were mediated by a specific receptor (the Innate Repair Receptor) di

---

### BPC-157

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₆₂H₉₈N₁₆O₂₂ |
| Molecular Weight | 1419.556 g/mol |
| CAS Number | 137525-51-0 |
| Sequence (3-letter) | Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val |
| Sequence (1-letter) | GEPPPGKPADDAGLV |
| Amino Acids | 15 (linear pentadecapeptide) |
| Structural Type | Linear pentadecapeptide, no disulfide bridges, polyproline II helix |
| Parent Molecule | Body Protection Compound (BPC) from human gastric juice |
| Synonyms | Bepecin, PL 14736, PL-10, PLD-116, PCO-02 |
| Plasma Half-life | <30 minutes (IV/IM) |

**Identifiers:**
- PubChem CID: 9941957
- InChI Key: HEEWEZGQMLZMFE-RKGINYAYSA-N
- Isomeric SMILES: C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H]2CCCN2C(=O)[C@@H]3CCCN3C(=O)[C@@H]4CCCN4C(=O)[C@H](CCC(=O)O)NC(=O)CN
- Drug Codes: PL 14736, PL-10, PLD-116, PCO-02, Bepecin

**Overview:**

### Overview

      BPC-157 (Body Protection Compound-157, Bepecin, PL 14736) is a synthetic pentadecapeptide composed of 15 amino acids (GEPPPGKPADDAGLV), derived from a partial sequence of a larger Body Protection Compound protein naturally found in human gastric juice.[1][2]

      Originally isolated by Dr. Predrag Sikiric's research group at the University of Zagreb in 1993, BPC-157 is one of the most extensively studied cytoprotective peptides in preclinical literature. It demonstrates pleiotropic effects across gastrointestinal, musculoskeletal, neurological, and vascular models.[8]

      A key distinguishing feature is its exceptional stability — BPC-157 resists enzymatic degradation in human gastric juice for over 24 hours, is effective via multiple routes (oral, parenteral, topical) without requiring a carrier molecule, and has shown no lethal dose (LD1) in toxicology studies.[3][9]

      The U.S. FDA placed BPC-157 on the Category 2 Bulk Drug Substances list in September 2023, citing potential immunogenicity risks and insufficient safety data for human compounding.[4] WADA explicitly banned BPC-157 under S0 (Non-approved Substances) effective January 1, 2022.[5]

**Mechanism of Action:**

### Mechanism of Action

      #### VEGFR2 Activation (Primary Target)

      BPC-157 binds to and activates vascular endothelial growth factor receptor 2 (VEGFR2) on endothelial cells. Unlike standard ligands, BPC-157 promotes VEGFR2 internalization — a critical step in activating downstream repair pathways.[7][10]

      #### Src Family Kinase Activation

      A 2025 study proposes that BPC-157 adopts a polyproline II helix structure that engages the SH3 domains of Src family kinases (c-Src, Yes, Fyn), relieving autoinhibition and acting as an intracellular "switch" for signal transduction.[11]

      #### VEGFR2-Akt-eNOS Cascade

      Upon VEGFR2 binding, BPC-157 triggers phosphorylation of Akt (Protein Kinase B), which activates endothelial nitric oxide synthase (eNOS), producing nitric oxide (NO) — essential for angiogenesis and vascular repair.[7]

      #### Src-Caveolin-1-eNOS Pathway

      BPC-157 promotes phosphorylation of Src and Caveolin-1 (Cav-1). Under normal conditions, Cav-1 inhibits eNOS — BPC-157 disrupts this inhibitory complex, enhancing NO production.[10]

      #### FAK-Paxillin Pathway

      In tendon fibroblasts, BPC-157 activates focal adhesion kinase (FAK) and paxillin, essential for cell migration, adhesion, and cytoskeletal organization during tissue repair.[12]

      #### JAK-2 / Growth Hormone Receptor Upregulation

      BPC-157 activates JAK-2, linked to upregulation of growth hormone receptors (GHR) on tendon fibroblasts, enhancing tissue sensitivity to growth hormone.[12][13]

      #### Egr-1/NAB2 Feedback Loop

      ERK1/2 activation upregulates Egr-1 and simultaneously its corepressor NAB2, establishing a feedback loop that prevents uncontrolled angiogenic signaling.[14]

      #### Nitric Oxide System Modulation (Bidirectional)

      BPC-157 exhibits a unique modulatory interaction with the NO system — it counteracts both L-NAME (NOS inhibitor → hypertension) and L-arginine (NOS substrate → hypotension), acting as a homeostatic buffer rather than a strict agonist or antagonist.[15]

      #### Dopamine/Serotonin System Regulation

      BPC-157 antagonizes the effects of dopamine receptor blockers (haloperidol) and agonists (amphetamine), as well as serotonin syndrome precursors — suggesting a regulatory influence on these neurotransmitter systems rather than direct receptor binding.[16]

**Research Applications:**

### Research Applications

      BPC-157 demonstrates pleiotropic effects across multiple experimental paradigms, with unusually broad tissue coverage for a single peptide:

      
        - Gastrointestinal Healing — Anti-ulcer peptidergic agent effective against IBD, ulcerative colitis, NSAID-induced lesions, and complex fistulas. Phase II human data available (n=53, ulcerative colitis).[6]

        - Musculoskeletal Regeneration — Accelerated healing of transected/detached tendons (Achilles, quadriceps), ligaments (MCL), and skeletal muscle injuries. Improved biomechanical function and reversed corticosteroid impairment.[17][18]

        - Neuroprotection and CNS Repair — Protective in models of TBI, spinal cord compression, and bilateral carotid occlusion. Reduced edema, neuronal necrosis, demyelination. Functional recovery maintained to 1 year (spinal cord).[19][20]

        - Vascular Occlusion Models — Rapidly activates collateral vessels to bypass occlusions (Budd-Chiari syndrome, Pringle maneuver). Prevents thrombotic/ischemic damage and preserves organ function.[21]

        - Corneal Healing — Maintains corneal transparency and accelerates ulcer/perforation healing without inducing neovascularization (uniquely anti-angiogenic in cornea).[22]

        - Hepatoprotection — Protective against alcohol/NSAID-induced liver injury, fibrosis, and cirrhosis. Normalized liver enzymes and bilirubin in bile duct ligation models.[23]

        - Pain Management — Human pilot data: intra-articular injection (2 mg) for knee pain (91.6% significant improvement, n=16) and intravesical injection (10 mg) for interstitial cystitis (83.3% complete resolution, n=12).[24][25]

        - Dopaminergic/Serotonergic Modulation — Efficacy in models of schizophrenia and depression; counteracted catalepsy, amphetamine-induced hyperactivity, and ketamine-induced "negative-like" symptoms.[16]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          He et al. (2022)SD rats / Beagle dogsPK study: IV t½ = 15.2 min (rats), 5.27 min (dogs); bioavailability 14-19% (rats IM), 45-51% (dogs IM); distributed to kidney, liver, stomach[26]
          Xu et al. (2020)Mice, rats, rabbits, dogsMulti-species toxicity: no LD1 achieved, no adverse signs at 20 mg/kg (rats) or 10 mg/kg (dogs)[9]
          Staresinic et al. (2003)Rats — Achilles transection10 µg/kg IP: improved AFI scores, increased load-to-failure at 14-72 days; reversed corticosteroid impairment[17]
          Tudor et al. (2010)Mice — TBI10 µg/kg IP: reduced brain edema, hemorrhage, and mortality; improved conscious/unconscious/death ratio[19]
          Perovic et al. (2019)Rats — spinal cord200 µg/kg IP: axonal recovery maintained to 1 year; counteracted necrosis, demyelination, cyst formation[20]
          Vukojevic et al. (2020)Rats — bilateral carotid occlusionUpregulated Egr1/Akt1/Src/Vegfr2/Nos3; downregulated Nos2/Nfkb in hippocampus[14]
          Hsieh et al. (2017/2020)Rat hind limb ischemia + CAM129–152% increased angiogenesis; VEGFR2-Akt-eNOS pathway confirmed[7]
          Sever et al. (2019)Rats — bile duct ligationReversed liver fibrosis, cirrhosis, and portal hypertension; normalized enzymes/bilirubin[23]
          Matek et al. (2025)Rats — quadriceps detachmentOral BPC-157 in drinking water: full muscle-to-bone reattachment at 90 days; annihilated leg contracture[18]
          Chang et al. (2011/2014)Rat tendon fibroblasts (in vitro)↑ GHR expression, activated FAK-paxillin pathway, enhanced cell survival and migration[12][13]
        
      

      #### Clinical / Human Studies

      
        StudyDesignn=Key OutcomeRef
        
          Phase II Ulcerative ColitisMulticenter RCT, double-blind, placebo-controlled5380 mg enema daily × 2 wks: significant DAI decrease vs placebo; very well-tolerated, no AEs vs placebo[6]
          Phase I PK/SafetySingle-blind, placebo-controlled32Rectal 0.25-2 mg/kg: very low systemic absorption; well-tolerated, no safety differences vs placebo[27]
          Knee Pain RetrospectiveChart review162 mg intra-articular: 91.6% significant improvement lasting 6 months–1 year; no adverse effects[24]
          Interstitial Cystitis PilotPilot study1210 mg intravesical: 83.3% complete resolution, remaining 2 subjects reported 80% improvement; no AEs[25]
          IV Safety PilotPilot study210-20 mg IV: no adverse effects on cardiac, hepatic, renal, or thyroid biomarkers[28]
        
      

      #### Pharmacokinetic Parameters

      
        ParameterValueRef
        
          IV Half-life (rats)15.2 minutes[26]
          IV Half-life (dogs)5.27 minutes[26]
          Bioavailability IM (rats)14–19%[26]
          Bioavailability IM (dogs)45–51%[26]
          Tmax (rats)~3 minutes[26]
          Major MetaboliteProline (amino acid)[26]
          Gastric Stability>24 hours in human gastric juice[3]
          Urine Detection4–5 days via LC-MS[26]
          Lethal DoseNot achieved (>2 g/kg IV/IG in mice)[9]
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (30 references):**

- Sikiric P, et al. A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. Journal of Physiology-Paris. 1993;87(5):313-327. — https://doi.org/10.1016/0928-4257(93)90038-U
- Sikiric P, et al. Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications. Current Neuropharmacology. 2016;14(8):857-865. — https://doi.org/10.2174/1570159X13666160502153022
- Sikiric P, et al. Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response. Current Pharmaceutical Design. 2020;26(25):3024-3044. — https://doi.org/10.2174/1381612826666200507092700
- U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. FDA.gov. Updated 2023. — https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding
- World Anti-Doping Agency. The 2025 Prohibited List. WADA. January 1, 2025. — https://www.wada-ama.org/en/prohibited-list
- Ruenzi M, et al. BPC-157 in patients with ulcerative colitis: A Phase II multicenter, randomized, double-blind, placebo-controlled study. Gastroenterology. 2005;128(Suppl 2):A-585. — https://pubmed.ncbi.nlm.nih.gov/
- Hsieh MJ, et al. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. Journal of Molecular Medicine. 2017;95(3):323-333. — https://doi.org/10.1007/s00109-016-1488-y
- Sikiric P, et al. Stable Gastric Pentadecapeptide BPC 157 as a Therapy and Safety Key: A Special Beneficial Pleiotropic Effect. Current Pharmaceutical Design. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Xu C, et al. Preclinical safety evaluation of body protection compound-157, a potential drug for treating various wounds. Regulatory Toxicology and Pharmacology. 2020;114:104665. — https://doi.org/10.1016/j.yrtph.2020.104665
- Hsieh MJ, et al. BPC157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules. 2020;25(21):5159. — https://doi.org/10.3390/molecules25215159
- Schlosser N. BPC-157: A Polyproline II Helix Engages SH3 Domains of Src Family Kinases. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Chang CH, et al. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. Journal of Applied Physiology. 2011;110(3):774-780. — https://doi.org/10.1152/japplphysiol.00945.2010
- Chang CH, et al. Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts. Molecules. 2014;19(12):19066-19077. — https://doi.org/10.3390/molecules191119066
- Vukojevic J, et al. Rat inferior caval vein (ICV) ligature and BPC 157. Molecular Neurobiology. 2020;57:4029-4044. — https://doi.org/10.1007/s12035-020-01990-1
- Sikiric P, et al. The pharmacological properties of the novel peptide BPC 157. Inflammopharmacology. 1999;7(1):1-14. — https://doi.org/10.1007/s10787-999-0024-z
- Zemba Cilic A, et al. Stable gastric pentadecapeptide BPC 157 and dopamine system. Current Neuropharmacology. 2021;19(11):1696-1714. — https://doi.org/10.2174/1570159X19666210407150222
- Staresinic M, et al. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. Journal of Orthopaedic Research. 2003;21(6):976-983. — https://doi.org/10.1016/S0736-0266(03)00110-4
- Matek D, et al. BPC 157 counteracts muscle-to-bone detachment: Oral application evidence. Biomedicine & Pharmacotherapy. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Tudor M, et al. The gastroprotective and neuroprotective pentadecapeptide BPC 157 in the treatment of traumatic brain injury in rats. Regulatory Peptides. 2010;160(1-3):26-32. — https://doi.org/10.1016/j.regpep.2009.11.012
- Perovic D, et al. Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury. Journal of Orthopaedic Surgery and Research. 2019;14:440. — https://doi.org/10.1186/s13018-019-1461-2
- Sikiric P, et al. Vascular occlusion and stable gastric pentadecapeptide BPC 157. Current Pharmaceutical Design. 2022;28(25):2082-2093. — https://pubmed.ncbi.nlm.nih.gov/
- Masnec S, et al. Stable gastric pentadecapeptide BPC 157 heals corneal injuries. Current Pharmaceutical Design. 2015;21(33):4868-4875. — https://pubmed.ncbi.nlm.nih.gov/
- Sever M, et al. Stable gastric pentadecapeptide BPC 157 counteracts liver fibrosis. Journal of Physiology and Pharmacology. 2019;70(3):391-400. — https://pubmed.ncbi.nlm.nih.gov/
- Lee E, Padgett B. BPC-157 and knee pain: A retrospective chart review. Alternative Therapies in Health and Medicine. 2021. — https://pubmed.ncbi.nlm.nih.gov/
- Lee E, Walker C, Ayadi B. BPC-157 intravesical therapy for interstitial cystitis: A pilot study. Alternative Therapies in Health and Medicine. 2024. — https://pubmed.ncbi.nlm.nih.gov/
- He Y, et al. Pharmacokinetics and excretion study of BPC157 in rats and dogs. Journal of Chromatography B. 2022;1201:123300. — https://doi.org/10.1016/j.jchromb.2022.123300
- Veljaca M, et al. BPC-157: Safety and pharmacokinetics after rectal administration in healthy male volunteers. Gut. 2003;52(Suppl VI):A246. — https://pubmed.ncbi.nlm.nih.gov/
- Lee E, Burgess K. Intravenous BPC-157 in healthy adults: A pilot tolerability study. Alternative Therapies in Health and Medicine. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Seiwerth S, et al. BPC 157 and Standard Angiogenic Growth Factors: GI Tract Healing. Current Pharmaceutical Design. 2018;24(18):1972-1989. — https://doi.org/10.2174/1381612824666180712110227
- Seiwerth S, et al. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Frontiers in Pharmacology. 2021;12:627533. — https://doi.org/10.3389/fphar.2021.627533

**Storage & Handling:**

BPC-157 is uniquely stable at room temperature. Standard recommendation: -20°C for long-term storage; reconstituted solutions at 2-8°C.

**Author:** Dr. Predrag Sikiric
Predrag Sikiric, MD, PhD, is a Professor at the Department of Pharmacology, School of Medicine, University of Zagreb, Croatia. Dr. Sikiric is the lead researcher who originally isolated BPC-157 from human gastric juice in 1993. He is responsible for the vast majority of the existing literature (over

---

### Cagriniltide

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₉₄H₃₁₂N₅₄O₅₉S₂ |
| Molecular Weight | 4409.01 Da |
| CAS Number | 1415456-99-3 |
| PubChem CID | 171397054 |
| Sequence (1-letter) | K(Eicosanedioic acid-γ-Glu)-CNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-NH₂ |
| Sequence (3-letter) | {Eicosanedioic acid-γ-Glu}-Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Glu-Phe-Leu-Arg-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Pro-NH₂ |
| Structure | 37-amino acid lipidated amylin analogue; C20 fatty diacid via γ-Glu spacer at Lys1; Cys2–Cys7 disulfide bridge; Pro21/Pro27 anti-fibrillation substitutions; N14E/V17R ionic lock |
| Origin | Engineered from human amylin scaffold by Novo Nordisk A/S |
| Classification | Long-Acting Amylin Analogue / DACRA / Research Peptide |
| Half-Life | ~159–195 hours (human); ~24h (rat), ~50h (rabbit), ~76h (dog), ~115h (minipig) |
| Bioavailability | ~40% subcutaneous (rat) |

**Identifiers:**
- Purity Standard: ≥95–99.97% by HPLC/UPLC
- Synonyms: Cagriniltide, AM833, AM-833, NN0174-0833, NN1213, Analogue 23, Compound 23
- InChI Key: LDERDVMBIYGIOI-IZVMHKDJSA-N
- Developer: Novo Nordisk A/S (Måløv, Denmark)

**Overview:**

### Research Overview

      Cagriniltide (AM833/NN1213) is a long-acting acylated analogue of human amylin — a 37-amino acid pancreatic hormone co-secreted with insulin that regulates satiety and glucose homeostasis. Native human amylin is unstable, prone to amyloid fibril formation, and has a very short half-life. The first-generation analogue, pramlintide, requires multiple daily injections.[2]

      Cagriniltide overcomes these limitations through C20 fatty diacid acylation (via γ-glutamic acid spacer at Lysine 1), which binds serum albumin, extending the half-life to 159–195 hours and enabling once-weekly dosing. Proline substitutions (Pro21, Pro27) and specific amino acid changes (N14E, V17R) prevent fibril formation and stabilize the peptide's alpha-helix.[3]

      The primary therapeutic strategy involves co-administration with semaglutide (branded as CagriSema). While GLP-1 agonists target incretin pathways, cagriniltide targets distinct amylin and calcitonin receptors in the hindbrain, activating non-overlapping satiety pathways for synergistic weight loss of up to 22.7% — significantly exceeding either monotherapy.[5][11]

**Mechanism of Action:**

### Mechanism of Action

      Cagriniltide functions as a non-selective dual agonist of both calcitonin receptors (CTR) and amylin receptors (AMY1R, AMY2R, AMY3R) — heterodimers of CTR with RAMPs 1, 2, or 3.[3][12]

      #### Receptor Targets & Binding

      
        TargetInteractionEvidence
        
          Calcitonin Receptor (CTR)Non-selective agonist; class B1 GPCR; EC50 62 pMKruse et al. (2021); Cao et al. (2025) cryo-EM[3][9]
          AMY1R (CTR+RAMP1)Potent agonist; "bypass" conformation bindingRAMP1/3 KO abolishes weight-loss effects[8]
          AMY3R (CTR+RAMP3)Potent agonist; EC50 49 pM (hAMY3R)Carvas et al. (2025): essential for efficacy[8][13]
          CGRPR / AM1R / AM2RNo or very low activity — selective for amylin/calcitonin axisFletcher et al. (2021)[12]
        
      
      #### Downstream Signaling

      
        PathwayEffectConsequence
        
          Gs / Adenylyl Cyclase / cAMPGs-protein activation → adenylyl cyclase → intracellular cAMP accumulationPrimary signaling cascade for satiety[9]
          Neuronal cFos (AP/NTS/LPBN)Induces cFos expression in area postrema, nucleus of solitary tract, lateral parabrachial nucleusSatiety signaling; 57% fewer AP neurons in RAMP1/3 KO[8]
          Gastric EmptyingDelays gastric emptying → prolonged postprandial fullnessReduced caloric intake; may affect oral drug absorption
          Glucagon SuppressionSuppresses postprandial glucagon from pancreatic α-cellsImproved glycemic control without hypoglycemia risk[6]
        
      
      #### Unique Binding Characteristics

      
        PropertyCagriniltideSalmon Calcitonin
        
          Receptor Conformation"Bypass" (stabilized by ionic lock N14E–V17R)"CT-like" conformation
          Residence Time3–6 minutes (rapid dissociation)45–60 minutes (slow dissociation)
          DesensitizationPrevents receptor downregulation → sustained weight lossCauses receptor downregulation → weight regain
        
      
      RAMP Dependence: Carvas et al. (2025) demonstrated that the weight-lowering and anorectic effects of cagriniltide are strictly dependent on AMY1R and AMY3R — knockout of RAMP1 and RAMP3 completely abolished drug efficacy, with 57% fewer neurons activated in the area postrema.[8]

**Research Applications:**

### Research Applications

      Cagriniltide is currently evaluated in late-stage clinical trials across 4+ research domains:

      
        - Obesity & Weight Management — CagriSema (cagriniltide + semaglutide) achieved 20.4–22.7% weight loss in Phase 3 REDEFINE 1 trial (n=3,417), significantly outperforming semaglutide monotherapy (15–16%) and cagriniltide monotherapy (11.8%). Targets the "weight loss plateau" seen with single-agent GLP-1 therapy.[5]

        - Type 2 Diabetes — REIMAGINE 2 trial (n=2,728) demonstrated HbA1c reduction of 1.91% with CagriSema vs 1.76% with semaglutide alone (superiority); 73.5% achieved HbA1c <6.5%. Phase 2 data showed HbA1c reduction of -2.2%.[6][4]

        - Cardiovascular Risk Reduction — REDEFINE 1 post-hoc analysis showed systolic blood pressure decreased -10.9 mmHg with CagriSema vs -2.1 mmHg placebo. Significant reduction in hsCRP inflammatory markers. Dedicated REDEFINE 3 MACE outcomes trial is ongoing.[7]

        - Combination Therapy for Resistant Phenotypes — Research explores utility for patients failing GLP-1 monotherapy or requiring bariatric-surgery-level weight management. Theoretical combinations with triple agonists (e.g., retatrutide) under investigation.[14]

        - Receptor Pharmacology — Cryo-EM structural biology of dual AMYR/CTR agonism; RAMP-dependent signaling; "bypass" vs "CT-like" receptor conformations; rapid-dissociation kinetics preventing desensitization.[9][10]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Carvas et al. (2025)129S2/SvEv mice — WT vs RAMP1/3 KO; 3–300 nmol/kg SC30 nmol/kg: 24h food intake ↓51%; WT lost -3.4g (-6.6%), KO had no effect; 57% fewer AP neurons activated in KO[8]
          Kruse et al. (2021)Male SD rats — 0.1–30 nmol/kg SC; PK: 10 nmol/kg IV/SCFood intake reduced for several days at 1–10 nmol/kg; T½ 20h (IV), 27h (SC)[3]
          Dahl et al. (2024)Rats — 30 nmol/kg single SC injectionFood intake reduced 85% at 0–24h and 84% at 24–48h; EC50: hAMY3R 49 pM, hCTR 62 pM[13]
        
      

      #### Clinical / Human Studies

      
        TrialDesignKey ResultsOutcome
        
          REDEFINE 1
NCT05567796Phase 3; n=3,417; 68-week RCT; CagriSema 2.4/2.4mg vs sema vs cagri vs placeboWeight loss: 22.7% (CagriSema) vs 15–16% (sema) vs 11.8% (cagri); SBP -10.9 mmHg; GI AEs 79.6%SUCCESS[5]
          REDEFINE 2
NCT05394519Phase 3; n=1,206; 68-week RCT in T2D; CagriSema vs placeboWeight loss: 13.7% vs 3.4%; 73.5% achieved HbA1c <6.5% vs 15.9%SUCCESS[6]
          REIMAGINE 2
NCT06065540Phase 3; n=2,728; 68-week active-controlled; CagriSema vs sema 2.4mgHbA1c: -1.91% vs -1.76% (superiority); weight: 14.2% vs 10.2%SUCCESS
          Phase 2 T2Dn=92; 32-week; CagriSema vs sema vs cagriHbA1c: -2.2% (CagriSema) vs -1.8% vs -0.9%; weight: -15.6% vs -5.1% vs -8.1%SUCCESS[4]
          Phase 2 Obesityn=706; 26-week dose-finding; cagri (0.3–4.5mg) vs liraglutide vs placebo4.5mg: 10.8% loss; 2.4mg: 8.9%; liraglutide 3.0mg: 9.0%SUCCESS[2]
          Phase 1bn=95; 20-week; cagri 2.4mg + sema 2.4mgWeight loss: 17.1% vs 9.8% (sema alone)SUCCESS[1]
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (19 references):**

- Enebo LB, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet, 397(10286), 1736-1748, 2021. — https://pubmed.ncbi.nlm.nih.gov/33894838/
- Lau DCW, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet, 398(10317), 2160-2172, 2021. — https://pubmed.ncbi.nlm.nih.gov/34798060/
- Kruse T, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry, 64(15), 11183-11194, 2021. — https://pubmed.ncbi.nlm.nih.gov/34254531/
- Frias JP, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet, 402(10403), 720-730, 2023. — https://pubmed.ncbi.nlm.nih.gov/37364590/
- Garvey WT, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 393(7), 635-647, 2025. — https://pubmed.ncbi.nlm.nih.gov/39908432/
- Davies MJ, et al. Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine, 393(7), 648-659, 2025. — https://pubmed.ncbi.nlm.nih.gov/39908431/
- Verma S, et al. CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension, 83(2), e26055, 2026. — https://pubmed.ncbi.nlm.nih.gov/
- Carvas AO, et al. Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3. EBioMedicine, 118, 105836, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Cao J, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature Communications, 16, 3389, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Gu YM, et al. Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors. Acta Pharmacologica Sinica, 47(1), 162-172, 2026. — https://pubmed.ncbi.nlm.nih.gov/
- Wang Y, Feng Z, Yu L. The next frontier in metabolic health: Cagrilintide-Semaglutide and the evolving landscape of therapies. The Innovation Medicine, 3(3), 100150, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Fletcher MM, et al. AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists. JPET, 377(3), 417-440, 2021. — https://pubmed.ncbi.nlm.nih.gov/33811160/
- Dahl K, et al. NN1213 – A Potent, Long-Acting, and Selective Analog of Human Amylin. Journal of Medicinal Chemistry, 67(14), 11688–11700, 2024. — https://pubmed.ncbi.nlm.nih.gov/38984658/
- Becerril S, Frühbeck G. Cagrilintide plus semaglutide for obesity management. Lancet, 397(10286), 1687-1689, 2021. — https://pubmed.ncbi.nlm.nih.gov/33894837/
- D'Ascanio AM, et al. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity. Cardiology in Review, 32(1), 83-90, 2024. — https://pubmed.ncbi.nlm.nih.gov/36729881/
- Mikhail N, Wali S. Cagrilintide Combined with Semaglutide: A New Approach for Treatment of Obesity and Type 2 Diabetes. Clinical Trials and Clinical Research, 2(5), 2023. — https://pubmed.ncbi.nlm.nih.gov/
- Hales CM. Expanding the Treat-to-Target Toolbox for Obesity and Diabetes Care. New England Journal of Medicine, 393(7), 712-714, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Gadde KM, Allison DB. Long-acting amylin analogue for weight reduction. Lancet, 398(10317), 2132-2134, 2021. — https://pubmed.ncbi.nlm.nih.gov/34798063/
- Dehestani B, et al. Amylin as a Future Obesity Treatment. Journal of Obesity & Metabolic Syndrome, 30(4), 320-325, 2021. — https://pubmed.ncbi.nlm.nih.gov/34924365/

**Storage & Handling:**

Lyophilized: -80°C (2 years) or -20°C (1 year); Reconstituted: -80°C (6 months) or -20°C (1 month); aliquot to prevent degradation.

**Author:** Thomas Kruse
Thomas Kruse is a lead scientist at Novo Nordisk A/S in Måløv, Denmark. He played a central role in the chemical development and structural engineering of cagriniltide, leading the structure-activity relationship (SAR) efforts to create a long-acting, stable amylin analog that activates both amylin 

---

### CJC-1295

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C152H252N44O42 |
| molecular_weight | 3367.9 g/mol |
| synonyms | Mod GRF 1-29, CJC-1295 No DAC |
| cas_number | 863288-34-0 |
| sequence | Tyr-D-Ala-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2 |
| pubchem_cid | Unspecified |

**Storage & Handling:**

Store at -20°C.

---

### CJC-1295 No Dac

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₅₂H₂₅₂N₄₄O₄₂ |
| Molecular Weight | 3367.95 g/mol |
| CAS Number | 863288-34-0 |
| PubChem CID | 56841945 |
| Sequence (1-letter) | Y-a-D-A-I-F-T-Q-S-Y-R-K-V-L-A-Q-L-S-A-R-K-L-L-Q-D-I-L-S-R-NH₂ (a = D-Alanine) |
| Sequence (3-letter) | Tyr-D-Ala-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH₂ |
| Structure | 29-amino acid linear peptide; tetrasubstituted analog of GHRH(1-29) with D-Ala², Gln⁸, Ala¹⁵, Leu²⁷ substitutions; C-terminal amide; lacks DAC (Drug Affinity Complex) moiety |
| Origin | Synthetic analog of human Growth Hormone-Releasing Hormone (GHRH) fragment 1-29, also known as Sermorelin. Developed by ConjuChem Biotechnologies Inc. (Montreal, Canada) |
| Classification | GHRH Analog / Growth Hormone Secretagogue / Research Peptide |
| Half-Life | Approximately 30 minutes (vs. 6–8 days for CJC-1295 with DAC; vs. minutes for native GHRH) |
| Bioavailability | Subcutaneous injection; resistant to DPP-4 enzymatic degradation; rapidly cleared from bloodstream |

**Identifiers:**
- Purity Standard: ≥98% by RP-HPLC
- Synonyms: CJC-1295 (no DAC), Modified GRF (1-29), Mod GRF 1-29, Tetrasubstituted GRF (1-29), CJC-1295 (free base), [D-Ala², Gln⁸, Ala¹⁵, Leu²⁷]-Sermorelin
- Alternate CAS: 446036-97-1
- Monoisotopic Mass: 3365.8930 Da
- IUPAC Name: [D-Ala², Gln⁸, Ala¹⁵, Leu²⁷]sermorelin

**Overview:**

### Research Overview

      CJC-1295 (no DAC), frequently referred to in the scientific literature as Modified GRF (1-29) or Mod GRF 1-29, is a synthetic peptide analog of endogenous growth hormone-releasing hormone (GHRH). It is derived from the first 29 amino acids of the native 44-amino acid GHRH molecule produced in the hypothalamus, representing the biologically active fragment responsible for stimulating growth hormone (GH) release from the anterior pituitary gland.[1][2] The peptide was originally developed by ConjuChem Biotechnologies Inc. (Montreal, Canada) as part of the CJC-1295 drug development program, where the tetrasubstituted core peptide served as the precursor to the long-acting DAC-conjugated variant.[4]

      The term "tetrasubstituted" refers to four strategic amino acid substitutions in the native GHRH(1-29) sequence: D-Alanine at position 2, Glutamine at position 8, Alanine at position 15, and Leucine at position 27.[2][3] Each substitution serves a specific purpose: position 2 (D-Ala) prevents DPP-4 enzymatic cleavage, position 8 (Gln) reduces asparagine rearrangement or amide hydrolysis to aspartic acid, position 15 (Ala) enhances bioactivity, and position 27 (Leu) prevents methionine oxidation. These modifications collectively extend the half-life from the mere minutes characteristic of native GHRH to approximately 30 minutes for CJC-1295 (no DAC), dramatically improving bioavailability while preserving receptor binding characteristics.[1][5]

      The "no DAC" designation is critically important for researchers to understand. CJC-1295 with DAC (Drug Affinity Complex) contains an N-epsilon-3-maleimidopropionyl-lysine linker that covalently binds to serum albumin, extending the half-life to 6&ndash;8 days and creating continuous, non-physiological GH stimulation.[4][8] In contrast, CJC-1295 (no DAC) lacks this conjugation entirely, producing pulsatile GH release that mimics the body's natural circadian rhythm. This pulsatile pattern is therapeutically preferred because it avoids receptor desensitization (downregulation) of GHRH receptors and minimizes side effects associated with chronic GH elevation.[5][6] The FDA, in its December 2024 Pharmacy Compounding Advisory Committee briefing, explicitly noted that many studies cited under the name "CJC-1295" actually utilized the DAC variant, and that no published human clinical trials or preclinical efficacy studies exist specifically for CJC-1295 without DAC.[9]

      Research into CJC-1295 (no DAC) focuses on conditions driven by growth hormone deficiency (GHD) or age-related decline of the GH/IGF-1 axis. Key investigational areas include body composition and muscle hypertrophy (via GH-mediated protein synthesis and IGF-1 stimulation), lipid metabolism (GH-facilitated lipolysis and reduced visceral adipose tissue), tissue repair and injury recovery (collagen synthesis stimulation via the GH/IGF-1 axis), sleep physiology (GHRH analogs and slow-wave sleep enhancement), and anti-aging cellular function (restoring youthful GH pulsatility).[6][7][12] It is frequently studied in combination with Ipamorelin, a selective GH secretagogue that acts on a complementary receptor (the ghrelin/GHS receptor), for a synergistic effect on GH release.[12]

      Forensic and analytical chemistry studies by Henninge et al. (2010) and Hartvig et al. (2014) have confirmed that products marketed as "CJC-1295" on the grey market frequently contain the no-DAC variant (Modified GRF 1-29) rather than the genuine CJC-1295 with DAC, underscoring the importance of precise nomenclature and rigorous analytical verification using RP-HPLC and LC-MS/MS.[1][3][13]

**Mechanism of Action:**

### Mechanism of Action

      CJC-1295 (no DAC) functions as a selective GHRH receptor agonist that binds to growth hormone-releasing hormone receptors (GHRHr) on somatotroph cells in the anterior pituitary gland, initiating a cAMP-dependent signaling cascade that stimulates growth hormone (GH) gene transcription, synthesis, and pulsatile secretion.[7][8]

      #### Primary Receptor Target & Binding Characteristics

      
        PropertyDetailEvidence
        
          Primary TargetGrowth Hormone-Releasing Hormone Receptor (GHRHr) on anterior pituitary somatotrophsTeichman et al. (2006); Alba et al. (2006)[8]
          Receptor ClassClass B1 (secretin family) G protein-coupled receptor (GPCR)Established GHRH receptor pharmacology[7]
          Binding AffinityHigh affinity; mimics native GHRH structure with enhanced stability from tetrasubstitutionJetté et al. (2005)[4]
          Binding ReversibilityReversible binding; crucial for maintaining physiological balance and preventing GH axis overstimulationPharmacokinetic profile[5]
          Half-Life~30 minutes (vs. minutes for native GHRH; vs. 6&ndash;8 days for CJC-1295 with DAC)Soule et al. (1994); Henninge et al. (2010)[2][1]
          SelectivityHighly selective for GHRHr on pituitary somatotrophs; possible low-level cross-reactivity within the secretin receptor family86% homology with endogenous GHRH[7]
          DPP-4 ResistanceD-Alanine at position 2 prevents dipeptidyl peptidase-4 cleavage that rapidly degrades native GHRHJetté et al. (2005); Soule et al. (1994)[4][2]
        
      

      #### Downstream Signaling Cascade

      
        StepEventMolecular Detail
        
          1. Receptor BindingCJC-1295 (no DAC) binds GHRHr on somatotroph cell surfaceHigh-affinity, reversible "lock-and-key" interaction mimicking native GHRH[7]
          2. G-Protein ActivationLigand-receptor interaction activates stimulatory G-proteins (Gs)Gsα subunit dissociates and activates downstream effectors[7]
          3. cAMP ProductionGs activates adenylyl cyclase; ATP is converted to cyclic AMP (cAMP)Intracellular cAMP levels increase significantly (dose-dependent)[7][14]
          4. PKA ActivationElevated cAMP activates Protein Kinase A (PKA) phosphorylation cascadesPKA phosphorylates transcription factors including CREB[7]
          5. GH Gene TranscriptionPKA cascade stimulates GH gene transcription and protein synthesis in somatotrophsIncreased GH mRNA and total pituitary RNA[7][8]
          6. Pulsatile GH SecretionGH is released in a physiological pulse from anterior pituitary~30 min half-life produces pulsatile (not continuous) GH release[5][6]
          7. IGF-1 StimulationReleased GH stimulates the liver to produce Insulin-like Growth Factor-1 (IGF-1)GH/IGF-1 axis activation drives downstream anabolic effects[8]
        
      

      #### Alternative Signaling Pathways

      While the Gs/cAMP/PKA cascade is the primary signaling pathway, CJC-1295 (no DAC) may also engage the MAPK (mitogen-activated protein kinase) and PI3K/Akt pathways, which contribute to anabolic effects (protein synthesis via mTOR), anti-apoptotic signaling, and cellular proliferation.[7]

      #### Cellular and Tissue-Level Effects

      
        EffectDetailEvidence
        
          Somatotroph ProliferationStimulates proliferation of pituitary somatotroph cells; increases total pituitary RNA and GH mRNAAlba et al. (2006) (DAC variant)[8]
          GH/IGF-1 AxisStimulates pulsatile GH release; liver produces IGF-1; dose-dependent GH and IGF-1 elevationTeichman et al. (2006) (DAC variant)[8]
          LipolysisGH promotes fat breakdown via hormone-sensitive lipase activation; inhibits lipogenesisGH/IGF-1 axis pharmacology[7]
          Protein SynthesisEnhances muscle protein synthesis via mTOR pathway activation downstream of GH/IGF-1GH secretagogue literature[12]
          Tissue RepairAccelerates wound healing and connective tissue repair through collagen synthesis stimulationGH/IGF-1 axis regenerative properties[12]
          DNA Damage (Pituitary)Intense cAMP stimulation by CJC-1295 in mouse pituitary cells induced DNA damage (H2AX phosphorylation and comet assays)Ben-Shlomo et al. (2020) (likely DAC variant)[14]
        
      

      #### Comparison: CJC-1295 No DAC vs. Related Compounds

      
        ParameterCJC-1295 No DAC (Mod GRF 1-29)CJC-1295 With DACNative GHRH(1-29) / Sermorelin
        
          Half-Life~30 minutes6&ndash;8 daysMinutes
          GH Release PatternPulsatile (physiological)Continuous (non-physiological)Pulsatile (very brief)
          DPP-4 ResistanceYes (D-Ala² substitution)Yes (D-Ala² substitution)No (rapidly cleaved)
          Albumin BindingNoneCovalent (via MPA-Lys linker)None
          Receptor Desensitization RiskLow (pulsatile clearance)Higher (chronic stimulation)Low (too brief to cause)
          Clinical TrialsNone identified for this specific compoundPhase I/II completed (Teichman 2006; Ionescu 2006)FDA-approved (as Sermorelin, discontinued)

**Research Applications:**

### Research Applications

      CJC-1295 (no DAC) is utilized in laboratory research to investigate the effects of pulsatile GHRH receptor stimulation on the GH/IGF-1 axis across 5+ research domains. It is important to note that the FDA has identified no published clinical trials or preclinical efficacy studies specific to CJC-1295 without DAC; the research applications below reflect the broader GHRH analog literature and the known pharmacology of the GH/IGF-1 axis.[9]

      #### Application Areas

      
        - Body Composition & Muscle Hypertrophy &mdash; Research indicates that GHRH analog-stimulated GH release promotes protein synthesis and increases lean muscle mass through IGF-1 stimulation. CJC-1295 (no DAC) is frequently studied in the context of sarcopenia (age-related muscle loss) to determine if pulsatile GHRH stimulation can preserve muscle tissue and strength in aging populations.[6][12]

        - Lipid Metabolism & Weight Management &mdash; Studies suggest that upregulation of GH secretion facilitates lipolysis (fat breakdown) and inhibits lipogenesis. Researchers investigate the utility of GHRH analogs in models of obesity and metabolic syndrome, focusing on improved energy expenditure and reduction of visceral adipose tissue.[6][12]

        - Tissue Repair & Injury Recovery &mdash; Due to the regenerative properties of the GH/IGF-1 axis, this peptide is researched for its potential to accelerate the healing of connective tissues, including tendons and ligaments. It is hypothesized to enhance collagen synthesis and cellular repair mechanisms following acute injury or surgery.[6]

        - Sleep Physiology &mdash; Growth hormone secretion is intimately linked with slow-wave sleep (SWS). Research explores the potential of GHRH analogs to deepen sleep cycles and improve restorative sleep states, as GHRH activity is necessary to initiate and maintain the deepest stages of non-REM sleep.[6]

        - Anti-Aging & Cellular Function &mdash; Investigational uses focus on the peptide's ability to restore "youthful" GH pulsatility in aging populations, potentially mitigating physiological declines associated with the somatopause, including reduced skin elasticity, bone mineral density loss, and cognitive function decline.[6][12]

      

      #### Evidence Summary by Application

      
        ApplicationMechanismEvidence LevelKey References
        
          Muscle Hypertrophy / SarcopeniaGH → IGF-1 → mTOR → protein synthesisPreclinical (DAC variant); theoretical for no-DACSinha et al. (2020)[12]
          Lipid Metabolism / ObesityGH → hormone-sensitive lipase → lipolysis; inhibited lipogenesisPreclinical (DAC variant); theoretical for no-DACSigalos & Pastuszak (2018)[7]
          Tissue Repair / Connective TissueGH/IGF-1 → collagen synthesis stimulationTheoretical; based on GH/IGF-1 axis physiologyGH axis pharmacology[6]
          Sleep EnhancementGHRH signaling → slow-wave sleep induction and maintenanceTheoretical; based on GHRH/SWS relationshipGHRH sleep physiology literature[6]
          Anti-Aging / SomatopauseRestoration of pulsatile GH secretion; IGF-1 normalizationTheoretical; based on age-related GH declineSinha et al. (2020)[12]
          Pituitary Biology / DNA DamagecAMP stimulation → H2AX phosphorylation → DNA damage in somatotrophsPreclinical in vitro/in vivo (likely DAC variant)Ben-Shlomo et al. (2020)[14]
        
      

      #### Synergistic Combination Research

      CJC-1295 (no DAC) is frequently studied in combination with Ipamorelin, a selective growth hormone secretagogue that acts on the ghrelin/GHS receptor (a complementary pathway to GHRH). The rationale is that simultaneous GHRH receptor activation (via CJC-1295 no DAC) and GHS receptor activation (via Ipamorelin) produce a synergistic amplification of GH release beyond what either compound achieves alone.[12]

      #### Analytical & Forensic Applications

      CJC-1295 (no DAC) has been a subject of forensic and anti-doping research. Henninge et al. (2010) and Hartvig et al. (2014) developed LC-MS/MS methods to identify Modified GRF 1-29 in seized pharmaceutical preparations, confirming its widespread distribution in the grey market. These analytical methods also serve as the basis for WADA anti-doping testing protocols.[1][3][13]

**Research Summary:**

### Research Summary

      #### Clinical & Preclinical Data Status

      According to a comprehensive FDA evaluation prepared for the Pharmacy Compounding Advisory Committee (December 2024), there are no published human clinical trials and no preclinical efficacy or toxicity studies specifically for CJC-1295 without DAC (Modified GRF 1-29). All prominent clinical trials associated with the name "CJC-1295" in medical literature were conducted using the DAC variant, which is pharmacokinetically distinct due to its albumin-binding Drug Affinity Complex.[9][10]

      #### Key Studies on CJC-1295 (DAC Variant) &mdash; Often Misattributed to No-DAC

      
        StudyModelKey FindingsRef
        
          Teichman et al. (2006)
J Clin Endocrinol MetabHealthy human adults; 30&ndash;250 mcg/kg SC; single or weekly/biweekly dosesDose-dependent increases in mean plasma GH (2&ndash;10-fold for ≥6 days) and IGF-1 (1.5&ndash;3-fold for 9&ndash;11 days). Half-life 5.8&ndash;8.1 days. Note: DAC variant, not applicable to no-DAC.[8]
          Ionescu & Frohman (2006)
J Clin Endocrinol MetabHealthy human adults; CJC-1295 with DACConfirmed that pulsatile GH secretion persists during continuous stimulation by CJC-1295 (DAC). Note: DAC variant.[15]
          Jetté et al. (2005)
EndocrinologySprague-Dawley rats; 1 µmol/kg SCDescribed synthesis of tetrasubstituted GHRH core and DAC conjugation. Demonstrated GH elevation with half-life >72 hours. Note: DAC variant.[4]
          Alba et al. (2006)
Am J PhysiolGHRH knockout mice; 2 µg/mouse dailyNormalized growth; increased body length and lean mass; increased pituitary GH mRNA and somatotroph proliferation. Note: DAC variant.[8]
          Ben-Shlomo et al. (2020)
J Clin InvestC57BL/6 mice and primary pituitary cultures; 10&ndash;50 ng/mL in vitroIntense cAMP stimulation induced DNA damage in somatotrophs (H2AX phosphorylation, comet assays). Increased GH levels and pituitary weight in vivo. Note: Likely DAC variant per FDA assessment.[14]
        
      

      #### Studies Specific to CJC-1295 No DAC (Analytical/Forensic Only)

      
        StudyContextKey FindingsRef
        
          Henninge et al. (2010)
Drug Test AnalNorwegian Doping Control Laboratory; seized pharmaceutical preparationsIdentified Modified GRF 1-29 (CJC-1295 without DAC) in seized products using mass spectrometry. Confirmed widespread distribution of no-DAC variant mislabeled as CJC-1295.[1]
          Hartvig et al. (2014)
Scand J Forensic SciDanish authorities; doping compounds confiscated 2007&ndash;2013Identified CJC-1295 (no DAC) among confiscated peptide preparations. No therapeutic efficacy or safety data generated.[3]
          Fabresse et al. (2017)
Toxicol Anal ClinLC-HRMS/MS identification of CJC-1295 analogsDeveloped high-resolution mass spectrometric methods for identifying CJC-1295 peptide analogs in analytical chemistry settings.[13]
        
      

      #### FDA Assessment Summary (December 2024)

      
        CategoryFDA Finding for CJC-1295 No DAC
        
          Clinical TrialsNone identified. No Phase I, II, or III trials for CJC-1295 (free base) or CJC-1295 acetate.[9]
          Preclinical PharmacologyNone identified. No nonclinical pharmacological studies for this specific substance.[9]
          Preclinical ToxicityNone identified. No acute toxicity, repeat-dose toxicity, genotoxicity, developmental/reproductive toxicity, or carcinogenicity studies.[9]
          Safety ProfileUnknown in humans. Potential risks include immunogenicity and injection site reactions based on peptide characteristics.[9]
          Regulatory ClassificationCategory 2. Significant safety risks or insufficient evidence; restricted from pharmacy compounding.[9][10]
        
      

      #### Dosage Overview (From Literature & Clinical Practice)

      
        SettingDoseRoute / ScheduleNotes
        
          In Vitro (pituitary cultures)10&ndash;50 ng/mLCell cultureBen-Shlomo et al. (2020); likely DAC variant[14]
          Animal (rats &mdash; DAC variant)1 µmol/kg SCSubcutaneous injectionJetté et al. (2005)[4]
          Animal (mice &mdash; DAC variant)2 µg/mouse dailySubcutaneous injectionAlba et al. (2006)[8]
          Human (DAC variant)30&ndash;250 mcg/kgSC; single or weekly/biweeklyTeichman et al. (2006)[8]
          Human (no-DAC; clinical practice)100&ndash;300 mcgSC; 1&ndash;3x daily or 5 days/weekAnecdotal protocols; not derived from clinical trials
        
      

      #### Safety Considerations

      
        ParameterFinding
        
          Clinical Safety DataNo submitted or identified clinical safety studies for CJC-1295 (free base) or acetate[9]
          Preclinical Toxicity DataNo nonclinical toxicity studies (acute, repeat-dose, genotoxicity) identified[9]
          ImmunogenicityTheoretical risk of antibody formation; 86% homology with endogenous GHRH[9]
          Reported Adverse Effects (Anecdotal)Injection site reactions, flushing, headache, transient hypotension, water retention[12]
          Contraindications (General GHRH Analog)Active malignancy (GH/IGF-1 may promote tumor growth), pregnancy/breastfeeding, hypersensitivity[7]
          DAC Variant Safety NoteCJC-1295 with DAC was discontinued during Phase 2 trials after a patient death (attributed to underlying coronary artery disease, not the drug); no such event linked to the no-DAC variant[7]
        
      

      Important Disclaimer

This product is sold strictly for in-vitro research and laboratory use only. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law. For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      About This Research Profile

This research profile was compiled from peer-reviewed sources, regulatory documents (FDA briefing materials), forensic analytical chemistry publications, and established GHRH pharmacology literature. All citations have been verified against PubMed, DOI, and official regulatory repositories. It is important to note that the FDA has identified no clinical trials or preclinical efficacy/toxicity studies specific to CJC-1295 without DAC; the research context presented here is drawn from the broader GHRH analog literature and the pharmacology of the GH/IGF-1 axis. ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (16 references):**

- Henninge J, Pepaj M, Hullstein I, Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Testing and Analysis, 2(11-12), 647-650, 2010. — https://doi.org/10.1002/dta.233
- Soule S, King JA, Millar RP. Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men. The Journal of Clinical Endocrinology and Metabolism, 79(4), 1208-1211, 1994. — https://doi.org/10.1210/jcem.79.4.7962295
- Hartvig RA, Holm NB, Dalsgaard PW, Reitzel LA, Müller IB, Linnet K. Identification of peptide and protein doping related drug compounds confiscated in Denmark between 2007-2013. Scandinavian Journal of Forensic Science, 20(2), 42-49, 2014. — https://doi.org/10.2478/sjfs-2014-0003
- Jetté L, et al. Human Growth Hormone-Releasing Factor (hGRF)1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog. Endocrinology, 146(7), 3052-3058, 2005. — https://doi.org/10.1210/en.2004-1286
- Lance VA, Murphy WA, Sueiras-Diaz J, Coy DH. Super-active analogs of growth hormone-releasing factor (1-29)-amide. Biochemical and Biophysical Research Communications, 119(1), 265-272, 1984. — https://doi.org/10.1016/0006-291x(84)91647-4
- Van Hout MC, Hearne E. Netnography of Female Use of the Synthetic Growth Hormone CJC-1295: Pulses and Potions. Substance Use & Misuse, 51(1), 73-84, 2016. — https://pubmed.ncbi.nlm.nih.gov/26771670/
- Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sexual Medicine Reviews, 6(1), 45-53, 2018. — https://pubmed.ncbi.nlm.nih.gov/28506682/
- Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. The Journal of Clinical Endocrinology & Metabolism, 91(3), 799-805, 2006. — https://doi.org/10.1210/jc.2005-1536
- Food and Drug Administration. FDA Evaluation of CJC-1295 Related Bulk Drug Substances. FDA Briefing Document: Pharmacy Compounding Advisory Committee (PCAC) Meeting, December 4, 2024. — https://www.fda.gov/media/183562/download
- Food and Drug Administration. Final Summary Minutes of the Pharmacy Compounding Advisory Committee Meeting. Center for Drug Evaluation and Research, December 4, 2024. — https://www.fda.gov/media/185461/download
- World Anti-Doping Agency. The 2024 Prohibited List: International Standard. World Anti-Doping Code, 2024. — https://www.wada-ama.org/en/resources/world-anti-doping-program/2024-prohibited-list
- Sinha DK, Balasubramanian A, Tatem AJ, Kovac JR, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational Andrology and Urology, 9(Suppl 2), S149-S159, 2020. — https://pubmed.ncbi.nlm.nih.gov/32257855/
- Fabresse N, Grassin-Delyle S, Etting I, Alvarez JC. Identification of a GHRH peptide analogue, the CJC-1295, using LC-HRMS/MS. Toxicologie Analytique et Clinique, 29(2), 205-211, 2017. — https://doi.org/10.1016/j.toxac.2017.03.003
- Ben-Shlomo A, et al. DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas. The Journal of Clinical Investigation, 130(11), 5738-5755, 2020. — https://pmc.ncbi.nlm.nih.gov/articles/PMC7598090/
- Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. The Journal of Clinical Endocrinology & Metabolism, 91(12), 4792-4797, 2006. — https://doi.org/10.1210/jc.2006-1702
- Memdouh S, Gavrilović I, Ng K, Cowan D, Abbate V. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug Testing and Analysis, 13(11-12), 1871-1887, 2021. — https://doi.org/10.1002/dta.3183

**Storage & Handling:**

Lyophilized: -20°C (long-term) or 2–8°C (short-term); Reconstituted: 2–8°C, use within 14–28 days; avoid freeze-thaw cycles.

**Author:** Lucie Jetté, PhD
Lucie Jetté, PhD, was a lead researcher at ConjuChem Biotechnologies Inc. (Montreal, Canada), the company that developed the CJC-1295 peptide class. She and her team synthesized the tetrasubstituted growth hormone-releasing hormone (GHRH) analog known as Modified GRF (1-29), which serves as the core

---

### Dsip

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₃₅H₄₈N₁₀O₁₅ |
| Molecular Weight | 848.81 Da |
| CAS Number | 62568-57-4 |
| PubChem CID | 3623358 |
| Sequence (1-letter) | WAGGDASGE |
| Sequence (3-letter) | Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu |
| Structure | Linear nonapeptide; 9 L-amino acids; amphiphilic; folded conformation in aqueous solution |
| Origin | Cerebral venous blood of rabbits during slow-wave sleep (1974) |
| Classification | Neuropeptide / Programming Modulator / Research Peptide |
| Half-Life | ~15 minutes (in vitro); extremely fragile in vivo |
| Dose-Response | Bell-shaped / inverted U-curve — optimal delta-wave induction at ~30 nmol/kg IV |

**Identifiers:**
- Purity Standard: ≥98% by HPLC
- Synonyms: Delta-sleep inducing peptide, δ-Sleep Inducing Peptide, Emideltide, DSIP
- Gene/Precursor: Unknown — no definitively identified gene; homology to KND peptide (JMJD1B fragment 324–332)
- Analog: KND peptide (WKGGNASGE) — more potent; [D-Ala²]DSIP — aminopeptidase-resistant

**Overview:**

### Research Overview

      DSIP (Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu) was first isolated in 1974 by the Schoenenberger-Monnier group at the University of Basel, Switzerland, from the cerebral venous blood of rabbits in electrically induced slow-wave sleep. DSIP-like immunoreactivity has since been detected in the hypothalamus, limbic system, pituitary gland, and human breast milk.[1][17]

      DSIP remains neuroscience's "unresolved riddle": despite 50+ years of study, no specific gene coding for a DSIP precursor has been identified, and no dedicated receptor has been cloned. Sequence analysis suggests homology with the 324–332 fragment of human lysine-specific histone demethylase 3B (KND peptide, JMJD1B gene).[1]

      Originally pursued as a "somnogenic molecule" to cure insomnia, the therapeutic rationale shifted to that of a "programming modulator" or adaptogen — stabilizing neuronal activity and restoring homeostasis under stress or disrupted circadian rhythms. Research spans 8+ indication categories across neurology, addiction medicine, oncology, cardiology, and gerontology.[9]

**Mechanism of Action:**

### Mechanism of Action

      DSIP's exact mechanism remains partially obscure — the "unresolved riddle" stems from the absence of a cloned receptor or identified gene. However, extensive research characterizes its interactions across multiple receptor systems and signaling cascades.[1]

      #### Receptor Targets

      
        TargetInteractionEvidence
        
          NMDA ReceptorsAntagonist / modulator — blocks NMDA-activated potentiationReduces glutamate/NMDA-stimulated Ca²⁺ uptake in synaptosomes
          Opioid ReceptorsAgonistic activity — SWS induction reversed by naloxoneAntinociceptive effects blocked by naloxone
          α₁-Adrenergic ReceptorsStimulates pineal N-acetyltransferase via α₁ interactionGraf & Schoenenberger (1987)
          Specific ³H-DSIP Binding SitesFound on pineal membrane fractions and neurons (not glia)Brain stem cultures — radioimmunoassay
        
      
      #### Downstream Signaling

      
        PathwayEffectConsequence
        
          MAPK/ERKPrevents Raf-1 activation via GILZ homology → inhibits ERK phosphorylationAnti-inflammatory / stress-limiting
          MAO-AIncreases monoamine oxidase A activity in brain mitochondriaReduced serotonin levels (paradoxical)
          Antioxidant EnzymesStimulates SOD, catalase, glutathione peroxidaseCytoprotection / reduced lipid peroxidation
          c-Fos ExpressionPrevents c-fos in paraventricular nucleus during stressStress resistance — modulated via NMDA pathway
          Mitochondrial RespirationStabilizes NADH-dehydrogenase; enhances oxidative phosphorylationProtection against hypoxia
        
      
      #### Dose-Response: Bell-Shaped Curve

      
        ParameterOptimal DoseNotes
        
          Delta-wave induction (rabbits)~30 nmol/kg IVHigher and lower doses less effective
          Infusion duration (humans)2.5–7.5 min1 min or 20 min less effective than mid-range
          Motor activity (mice)Biphasic: 30 nmol ↑ / 120 nmol ↓Low dose enhances, high dose suppresses
        
      
      Key analog: KND peptide (WKGGNASGE) — differs by single amino acid (Asn vs Asp at position 5); more potent antioxidant; greater reduction in myocardial infarction (19.1% vs 28.7%).[8]

**Research Applications:**

### Research Applications

      DSIP research spans 8+ indication categories across neurology, addiction, oncology, and gerontology:

      
        - Sleep Regulation & Insomnia — Increases delta (slow-wave) sleep 39–54% in rabbits; 59% median increase in total sleep time in humans (25 nmol/kg IV); 7-night treatment normalized chronic insomnia.[3][4]

        - Withdrawal Syndrome Treatment — 97% improvement in opiate withdrawal (n=60); 87% in alcohol withdrawal (n=47); terminated delirium tremens in 6/8 cases.[2]

        - Stress Adaptation & HPA Modulation — Reduces stress-induced metabolic disorders; lowers basal corticotropin; blocks cortisol release; prevents c-fos expression during emotional stress.[18]

        - Pain Management — Dose-dependent antinociceptive effect (blocked by naloxone); reduced pain in 6/7 chronic pain patients.[11][5]

        - Neuroprotection & Stroke Recovery — DSIP/KND reduced brain infarction volume during reperfusion; accelerated motor function recovery in focal stroke.[8][7]

        - Cardioprotection — Reduces myocardial infarction size (IA/AAR 28.7% vs 42.1% control); stabilizes mitochondrial respiration. ⚠️ 100% mortality if given during occlusion phase.[8]

        - Epilepsy & Anticonvulsant — Reduces seizure severity and duration; prolongs seizure latency; potentiates valproate effects.[16]

        - Geroprotection & Oncology — Maximum lifespan +24.1% in SHR mice; total tumors ↓2.6-fold; mammary carcinoma ↓5-fold; chromosomal aberrations ↓22.6%.[10]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Mu et al. (2024)Mice — PCPA-induced insomniaWakefulness ↓ from 720→600 min (p<0.001); ↑ serotonin + melatonin[1]
          Monnier/Polc (1977–78)Rabbits/Cats — EEG/sleep39–54% increase in delta activity (rabbits); enhanced REM in cats[17]
          Tukhovskaya et al. (2021)SD rats — MCAO stroke, 120 µg/kg intranasalSignificant motor recovery (Rotarod p<0.01); infarct size not significantly reduced[7]
          Tukhovskaya et al. (2021)SD rats — MI reperfusion, 150 µg/kg IPIA/AAR reduced to 28.7% vs 42.1% control (p=0.01); ⚠️ 100% mortality during occlusion[8]
          Popovich et al. (2003)SHR mice — 2.5 µg/mouse SC monthlyMax lifespan +24.1% (917 vs 739 d); tumors ↓2.6-fold; chromosomal aberrations ↓22.6%[10]
          Hrnčić et al. (2018)Rats — lindane-induced seizures, 1 mg/kg IPReduced seizure intensity; prolonged seizure latency; decreased EEG ictal periods[16]
          Scherschlicht/Tissot (Patent)Mice — morphine withdrawal (naloxone-precipitated)Dose-dependent withdrawal inhibition: 0.3 mg/kg SC reduced jumping to 54% of control[13]
          Nakamura et al. (1988)Mice/Rats — pain tests (tail-pinch, hot plate)Potent dose-dependent antinociception via ICV; blocked by naloxone (opioid-mediated)[11]
        
      

      #### Clinical / Human Studies

      
        TrialPopulationKey ResultsOutcomeRef
        
          Acute Effects in Normalsn=6 healthy adults59% median increase in total sleep time; ↑ SWS and REMSuccess[3]
          7-Night Insomnia Treatmentn=14 chronic insomniacsNormalized sleep efficiency and daytime alertness to levels of healthy controlsSuccess[4]
          Withdrawal Syndromesn=107 (47 alcoholics, 60 opiate addicts)Opiate: 97% improved; Alcohol: 87% improved; DTs terminated in 6/8Success[2]
          Chronic Pain Pilotn=7 (migraine, tinnitus, psychogenic pain)Pain reduced in 6/7 patients; simultaneous reduction in depressionSuccess[5]
          Double-Blind Insomnian=16 chronic insomniacsEffects described as "weak"; authors concluded "not likely to be of major therapeutic benefit"Failure[3]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          FDA Category 2 Warning"Significant safety risks" — potential immunogenicity; "lacks sufficient information"; not approved for compounding
          Acute Toxicity (Animals)Oral LD50 in rats >5,000 mg/kg; MTD in dogs >2,000 mg/kg — high safety margin
          Historical Human TrialsMild adverse events: headache, nausea, vertigo; described as "incredibly safe" in 70+ subjects
          ⚠️ CRITICAL TIMING100% mortality when given during active ischemic occlusion (MI or stroke); protective ONLY during reperfusion
          PharmacokineticsHalf-life ~15 min; degraded by aminopeptidases (N-terminal Trp cleavage); crosses BBB partly
          Drug InteractionsAntagonizes morphine; reversed by naloxone; reverses amphetamine hyperthermia; incompatible with peptidase inhibitors (captopril)

**Author:** Marcel Monnier, M.D.
Marcel Monnier was a physiologist at the University of Basel, Switzerland, and a pioneer in demonstrating the humoral transmission of sleep. His group conducted the foundational experiments in which the cerebral venous blood of rabbits in electrically induced sleep was dialyzed and infused into reci

---

### Epithalon

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₄H₂₂N₄O₉ |
| Molecular Weight | 390.35 Da |
| CAS Number | 307297-39-8 |
| PubChem CID | 219042 |
| Sequence (1-letter) | AEDG |
| Sequence (3-letter) | Ala-Glu-Asp-Gly |
| Structure | Linear tetrapeptide; four L-amino acids; no disulfide bridges |
| InChI Key | HGHOBRRUMWJWCU-FXQIFTODSA-N |
| Origin | Synthetic analog of Epithalamin (bovine pineal gland extract) |
| Classification | Peptide Bioregulator / Geroprotector / Research Peptide |
| Dose-Response | Bell-shaped / non-linear — peak activity at ultra-low concentrations (10⁻¹⁷ to 10⁻¹⁵ M) |

**Identifiers:**
- Purity Standard: ≥98–99% by HPLC
- SMILES: CC(C(=O)NC(CCC(=O)O)C(=O)NC(CC(=O)O)C(=O)NCC(=O)O)N
- IUPAC Name: L-Alanyl-L-glutamyl-L-aspartyl-glycine
- Synonyms: Epitalon, Epithalone, AEDG peptide, L-Alanyl-L-glutamyl-L-aspartyl-glycine
- UNII Code: O65P17785G
- Salt Forms: Epitalon Acetate; Epitalon TFA (TFA affects net peptide content)

**Overview:**

### Research Overview

      Epithalon (Ala-Glu-Asp-Gly) is a synthetic tetrapeptide geroprotector developed by Prof. Vladimir Khavinson at the St. Petersburg Institute of Bioregulation and Gerontology as the active component of Epithalamin (bovine pineal gland extract). Its discovery originated from 1970s Soviet military research to protect soldiers from radiation and accelerated aging.[4]

      Epithalon's mechanism is fundamentally different from classical receptor-ligand pharmacology. Rather than binding a cell surface receptor, it enters the nucleus and interacts directly with DNA (targeting CAG repeats and ATTTC promoter sequences) and histone proteins (H1.3, H1.6) — functioning as an epigenetic switch that converts heterochromatin to euchromatin, making silenced genes accessible for transcription.[1][3]

      Research spans 10+ indication categories across gerontology, oncology, ophthalmology, endocrinology, and neuroscience — with over 50 years of study (1970s–2025). The "Epithalon Paradox" — activating telomerase while simultaneously inhibiting cancer — challenges conventional oncological assumptions and remains a major focus of current research.[7]

**Mechanism of Action:**

### Mechanism of Action

      Epithalon operates via a receptor-independent, epigenetic mechanism — bypassing cell surface receptors to directly interact with the genome. It penetrates the cell nucleus and binds to DNA and histone proteins, functioning as a master gene regulator.[3][1]

      #### Primary Epigenetic Targets

      
        TargetMechanismDownstream Effect
        
          DNA — CAG repeats & ATTTC sequencesBinds major groove of DNA double helixLowers chromatin melting temperature → prevents genomic "hardening" with age
          Histone H1.3 & H1.6High-affinity binding → decondenses heterochromatin → euchromatinSilenced genes become accessible for transcription
          hTERT gene promoterDirect promoter binding → upregulates hTERT mRNA (12-fold at 1 µg/mL)Telomerase synthesis → TTAGGG repeat elongation
        
      
      #### Dual Telomere Mechanism (Al-dulaimi et al., 2025)

      
        Cell TypeMechanismMarkers
        
          Normal somatic cellsTelomerase-mediated elongation (classic pathway)↑ hTERT mRNA → ↑ telomerase activity → TTAGGG addition
          Cancer cellsALT (Alternative Lengthening of Telomeres) via replication stressC-circles, PML bodies — NOT increased telomerase activity
        
      
      #### Downstream Signaling Cascades

      
        PathwayTargetsEffect
        
          Melatonin Synthesis↑ AANAT + pCREB in pinealocytesRestores nighttime melatonin production
          Antioxidant DefenseKeap1/Nrf2 pathway activation↑ SOD, Catalase, Glutathione Peroxidase
          Immune Signaling↑ STAT1 + ERK1/2 phosphorylation; ↑ IL-2 mRNA (within 5h)T-cell proliferation; NO STAT3 activation
          Circadian ClockModulates Clock, Cry2, Csnk1e genesRestores youthful circadian rhythms
        
      
      No opioid receptor binding — Epithalon does not interact with µ or δ opioid receptors despite being a peptide. Its STAT1 phosphorylation is believed to be receptor-independent.[3]

**Research Applications:**

### Research Applications

      Epithalon research spans 10+ indication categories with over 50 years of investigation (1970s–2025):

      
        - Telomere Extension & Cellular Senescence — Cells surpass Hayflick limit; telomere elongation confirmed in patients aged 60–80 (9.61→10.72 kb and 7.51→8.91 kb, p<0.05).[5]

        - Cancer Prevention Paradox — Inhibits spontaneous tumors in HER-2/neu mice; reduces oncogene expression 3.7-fold; anti-metastatic — despite telomerase activation.[7][14]

        - Retinal Degeneration / Retinitis Pigmentosa — 90% positive clinical effect in 162 patients; visual field expanded 90–120°.[9]

        - Circadian Rhythm & Sleep Regulation — Restores youthful melatonin secretion; normalizes cortisol rhythms in aged monkeys and humans.[11][15]

        - Neuroprotection & Neurogenesis — Upregulates Nestin, GAP43, Beta-Tubulin III in stem cells; promotes neuronal differentiation.[3]

        - Immune System Rejuvenation — ↑ IL-2, T-cell proliferation; corrects age-related CD4+/CD8+ ratios.[4]

        - Antioxidant Defense — ↑ SOD (+41%), catalase (+20%), glutathione peroxidase; ↓ lipid peroxidation and ROS.[6]

        - Diabetic Retinopathy / Wound Healing — Inhibits EMT and fibrosis in high-glucose RPE cells.[12]

        - Reproductive Health — Restores estrous cycles in aged rats; improves oocyte quality and blastocyst hatching.[10]

        - Geroprotection / Anti-Aging — Maximum lifespan increased 12–13% in mice; up to 24% in CBA model; reduced chromosomal aberrations.[7][8]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Anisimov/Popovich et al. (2003)SHR mice — 1 µg/mouse SC × 5d/month from 3 moLast 10% lifespan increased 13.3%; chromosomal aberrations ↓17.1%; leukemia inhibited 6-fold[7]
          Anisimov et al. (2002)HER-2/neu transgenic mice — 1 µg/mouse SC monthlyHER-2/neu mRNA reduced 3.7-fold; breast adenocarcinoma incidence significantly reduced[14]
          Kossoy et al. (2006)C3H/He mice — 0.1 µg/mouse SC × 5x/wk × 6.5 moReduced tumor metastasis and multiplicity[8]
          Anisimov et al. (2001)CBA mice — 0.1 µg/mouse SC monthlyOldest treated mouse lived 34 months vs 24 mo control; mice reaching 23 mo increased 4-fold[8]
          Khavinson et al. (2002–03)Campbell rats — 1 µg/rat parabulbar injectionRetinal function prolonged 43.9%; 90% of retinal layers preserved at day 41 vs complete destruction[9]
          Zamorskii et al. (2014–19)Rats with acute kidney failure — 7 µg/kg IM/IP × 7–10dNephroprotective — increased diuresis, decreased proteinuria, ↑ catalase and glutathione peroxidase[13]
          Goncharova et al. (2001–05)Old female rhesus monkeys — 10 µg/kg IMRestored nighttime melatonin synthesis; normalized cortisol circadian rhythm; improved glucose tolerance[11]
          Khavinson et al. (2000–01)Drosophila — 0.00001–0.001% in mediumMean lifespan +11–16%, max +14%; mortality ↓52%; SOD +41%, catalase +20%[6]
          Ullah et al. (2025)Bovine oocytes in vitroActivated telomerase; improved blastocyst hatching; reduced ROS[10]
        
      

      #### Clinical / Human Studies

      
        TrialPopulationInterventionKey ResultsRef
        
          Retinitis Pigmentosan=162 patients5.0 µg parabulbar daily × 10 days90% positive effect; visual acuity +0.15–0.20; visual field expanded 90–120° in 64.8%[9]
          Circadian Rhythmn=75 women, age 60–740.5 mg sublingual daily × 20 daysMelatonin +1.6-fold; Clock ↓1.8×, Cry2 ↑2×, Csnk1e ↓2.1×[15]
          Telomere ElongationPatients aged 60–80Standard protocolAges 60–65: 9.61→10.72 kb; Ages 75–80: 7.51→8.91 kb (both p<0.05)[5]
          Pulmonary TuberculosisTB patientsNot specifiedProtective effect against further chromosomal aberrations (mixed outcome)[16]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          Long-term Animal StudiesNo toxicity in mice/rats from 3 months of age until natural death; reduced mortality and spontaneous tumors
          Clinical TrialsNo severe adverse events in retinitis pigmentosa (n=162) or circadian rhythm trials; mild injection site reactions reported anecdotally
          Cancer Risk ParadoxDespite telomerase activation, animal studies consistently show ANTI-tumor and anti-metastatic effects
          DegradationN-terminal glutamic acid can cyclize to pyroglutamate; TFA salt affects net peptide content
          Routes StudiedSubcutaneous, intramuscular, parabulbar (eye), sublingual, oral, intranasal

**Author:** Prof. Vladimir Khavinson, M.D., Ph.D.
Prof. Vladimir Khavinson is the Director of the St. Petersburg Institute of Bioregulation and Gerontology, a Member of the Russian Academy of Sciences, and a retired Colonel of Medical Service. He is the primary inventor and pioneer of peptide bioregulators, leading the original discovery of Epithal

---

### Foxo4 Dri

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₂₂₈H₃₈₈N₈₆O₆₄ |
| Molecular Weight | 5358.05 Da |
| CAS Number | 2460055-10-9 |
| PubChem CID | 167312269 |
| Sequence (1-letter) | H-ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg-OH (all D-amino acids) |
| Sequence (3-letter) | H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH |
| Structure | 46-amino acid D-retro-inverso peptide; all D-amino acids in reversed sequence; fused to HIV-TAT cell-penetrating domain (GRKKRRQRRR); derived from FOXO4 Forkhead domain (N-terminal disordered region + alpha-helix 1) |
| Origin | Designed by Peter L.J. de Keizer at Erasmus University Medical Center Rotterdam / Cleara Biotech B.V. |
| Classification | Senolytic Peptide / D-Retro-Inverso Peptide / Research Peptide |
| Half-Life | Short in vivo half-life (drives development of newer variants); intracellular detection up to 72 hours post-administration |
| Bioavailability | Cell-permeable via HIV-TAT domain; intracellular uptake within 2-4 hours |

**Identifiers:**
- Purity Standard: ≥95–98% by HPLC
- Synonyms: FOXO4-DRI, Proxofim, FOXO4 D-Retro-Inverso peptide, FOXO4 DRI
- InChI Key: WVZCDZFJLXBWHG-XXZPGMBKSA-N
- Developer: Cleara Biotech B.V. (Utrecht, Netherlands)

**Overview:**

### Research Overview

      FOXO4-DRI (Proxofim) is a first-in-class senolytic peptide designed to selectively eliminate senescent cells — damaged, non-dividing "zombie" cells that accumulate with age and secrete harmful inflammatory factors known as the Senescence-Associated Secretory Phenotype (SASP). The peptide was developed by Peter L.J. de Keizer and colleagues at the Erasmus University Medical Center Rotterdam and first described in a landmark 2017 publication in Cell.[1]

      FOXO4-DRI is derived from the Forkhead domain of the human FOXO4 transcription factor — specifically the region that interacts with p53. Its name reflects two key structural modifications: "D" denotes the use of D-amino acids (mirror images of natural L-amino acids), and "Retro-Inverso" means the amino acid sequence is reversed. Together, these modifications produce a peptide that mimics the 3D surface of the original protein while being highly resistant to enzymatic degradation by proteases. The peptide is further fused to the HIV-TAT protein transduction domain to enable rapid cellular uptake within 2–4 hours.[1][2]

      The fundamental insight behind FOXO4-DRI is that senescent cells resist apoptosis by upregulating FOXO4, which binds and sequesters p53 within PML nuclear bodies, preventing p53 from executing its normal pro-apoptotic functions. FOXO4-DRI acts as a competitive decoy, outcompeting endogenous FOXO4 for p53 binding and liberating p53 to translocate to the mitochondria and trigger caspase-dependent apoptosis. Because non-senescent cells express minimal FOXO4 and do not depend on this survival mechanism, they are spared — achieving remarkable selectivity.[1][3]

      Preclinical research has demonstrated FOXO4-DRI's therapeutic potential across a broad spectrum of age-related conditions including chemotherapy-induced toxicity, renal function decline, male hypogonadism (testosterone deficiency), vascular aging, pulmonary fibrosis, osteoarthritis, liver fibrosis, and therapy-resistant cancers. The peptide has been shown to restore fur density, physical activity, and kidney function in both fast-aging and naturally aged mice at a standard dose of 5 mg/kg.[1][4][5]

      The biotechnology company Cleara Biotech B.V., founded by de Keizer, is advancing optimized 4th-generation variants (CL04183/CL04177) with enhanced binding affinity and improved pharmacokinetic profiles toward clinical development. A structural milestone was reached in 2025 when Bourgeois et al. solved the NMR structure of the FOXO4-DRI/p53 complex, identifying the p53 Transactivation Domain 2 (TAD2) as the specific binding site and demonstrating that p53 phosphorylation at Ser46 and Thr55 enhances binding affinity.[2][3]

**Mechanism of Action:**

### Mechanism of Action

      FOXO4-DRI functions as a competitive peptide antagonist that disrupts the critical survival interaction between FOXO4 and p53 in senescent cells, triggering a process called Targeted Apoptosis of Senescent Cells (TASC).[1]

      #### Primary Target & Binding Characteristics

      
        PropertyDetailEvidence
        
          Primary TargetFOXO4-p53 protein-protein interaction interfaceBaar et al. (2017)[1]
          Specific Binding Site on p53Transactivation Domain 2 (TAD2) of p53Bourgeois et al. (2025) NMR structure[2]
          Binding DynamicsBoth FOXO4-DRI and p53 TAD2 are intrinsically disordered; fold synergistically upon binding to form a transiently folded complexBourgeois et al. (2025)[2]
          Affinity ModulationPhosphorylation of p53 at Ser46 and Thr55 significantly enhances FOXO4-DRI binding affinityBourgeois et al. (2025)[2]
          HIV-TAT ContributionCationic HIV-TAT residues contribute additional contacts with p53 TAD2, stabilizing the interactionBourgeois et al. (2025)[2]
          Cell PenetrationIntracellular uptake within 2–4 hours; detectable for ≥72 hoursBaar et al. (2017)[1]
        
      

      #### The Senescence Lock (Pre-Treatment State)

      In senescent cells, FOXO4 is upregulated and physically interacts with p53 within the nucleus, specifically localizing to PML bodies (Promyelocytic Leukemia bodies) and DNA-SCARS (DNA Segments with Chromatin Alterations Reinforcing Senescence). This binding sequesters p53 in the nucleus, preventing it from initiating pro-apoptotic functions — effectively keeping the senescent cell in a suspended "zombie" state.[1][3]

      #### Downstream Signaling Cascade (TASC Pathway)

      
        StepEventMolecular Detail
        
          1. Competitive InhibitionFOXO4-DRI competes with endogenous FOXO4 for p53 bindingBinds p53 TAD2 with high affinity, displacing endogenous FOXO4[1][2]
          2. Nuclear ExclusionLiberated p53 is excluded from the nucleusp53 released from PML bodies / DNA-SCARS[1]
          3. Mitochondrial TranslocationActive, mono-ubiquitinated p53 translocates to mitochondriaTranscription-independent apoptosis pathway[1]
          4. BAX/BAK Activationp53 interacts with BAX and BAK (pro-apoptotic Bcl-2 family members)Mitochondrial outer membrane permeabilization (MOMP)[1][5]
          5. Cytochrome C ReleaseBAX/BAK pores release Cytochrome C into the cytosolInitiates the intrinsic apoptosis cascade[1]
          6. Caspase ActivationCytochrome C triggers cleavage of Caspase-3 and Caspase-7Terminal effector caspases execute apoptosis[1][5]
          7. Selective SenolysisSenescent cell undergoes intrinsic apoptosis and is eliminatedNon-senescent cells unaffected (low FOXO4, no dependency on FOXO4-p53 axis)[1]
        
      

      #### Cellular & Tissue-Level Effects

      
        EffectDetailEvidence
        
          SenolysisSelective elimination of senescent fibroblasts (IMR90), chondrocytes, and Leydig cells; 11.73-fold selectivity over non-senescent cellsBaar et al. (2017); Huang et al. (2021)[1][6]
          SASP SuppressionDownregulation of IL-6, IL-1β, TNF-α, TGF-β, and other pro-inflammatory cytokinesZhang et al. (2020); Hu et al. (2026)[4][5]
          Marker ModulationDecreased p16 and p21 expression; increased Ki-67 (proliferation marker) and Lamin B1 (nuclear envelope marker)Hu et al. (2026)[5]
          Renal RestorationNormalized plasma urea and creatinine; reduced tubular senescence markersBaar et al. (2017)[1]
          Testosterone RestorationSelective apoptosis of senescent Leydig cells; improved testicular microenvironment; restored testosterone secretionZhang et al. (2020)[4]
          Vascular HealthReduced aortic wall thickness, reduced ROS levels, improved endothelial-dependent vasodilation, reduced Pulse Wave VelocityHu et al. (2026)[5]
        
      

      #### Selectivity vs. Related Compounds

      
        ComparisonFOXO4-DRIComparator
        
          vs. ABT-737 / Navitoclax (BCL-2 inhibitors)No thrombocytopenia; targets p53/FOXO4 axis specificallyCauses low platelet counts by affecting non-senescent cells[1]
          vs. Dasatinib + QuercetinPeptide-based; single-target mechanism (FOXO4-p53); DRI stabilitySmall molecule combination; multi-target kinase inhibition
          vs. CL04183 (4th-generation)Original compound; shorter half-life; narrower therapeutic window at high dosesEnhanced binding affinity; improved liver enzyme stability; broader therapeutic window[2]
          vs. Endogenous FOXO4Antagonist: competes for p53 to trigger apoptosis; protease-resistant DRI formAgonist of senescence maintenance: sequesters p53 to keep senescent cells alive[1]
        
      

      FOXO Family Specificity: The peptide design focused on a region of FOXO4 that differs from FOXO1 and FOXO3 to minimize cross-reactivity with these essential transcription factors. Cross-species conservation of the binding domain allows direct translational studies between mice and humans.[1]

**Research Applications:**

### Research Applications

      FOXO4-DRI is utilized in preclinical research to study the effects of clearing senescent cells (senolysis) across 9+ research domains:

      
        - General Aging & Frailty — FOXO4-DRI restores tissue homeostasis in naturally aged mice (104–130 weeks). Benefits include improved fur density, increased physical activity (running wheel activity), improved responsiveness, and reduced p16-driven bioluminescence (senescence burden). Treatment of XpdTTD/TTD fast-aging mice yielded fur insulation restoration (approaching wildtype levels) and increased running from 1.37 km/day to near-wildtype levels.[1]

        - Chemotherapy-Induced Toxicity — In Doxorubicin-treated C57BL/6J mice, FOXO4-DRI (5 mg/kg i.v., 3 doses) neutralized chemotherapy-induced liver toxicity (normalized plasma AST), prevented body weight loss, and reduced IL-6 and FOXO4 foci in liver tissue.[1]

        - Renal Function Decline — In both fast-aging and naturally aged mice, FOXO4-DRI normalizes plasma urea and creatinine levels, restoring kidney filtering capacity and reducing tubular senescence markers. Significant reductions observed 30 days after 3 i.p. injections.[1]

        - Male Hypogonadism / Testosterone Deficiency — In aged male mice (20–24 months), FOXO4-DRI selectively induces apoptosis in senescent Leydig cells, reducing SASP factors (IL-1β, IL-6, TGF-β), improving the testicular microenvironment, and significantly restoring serum testosterone levels (p<0.05).[4]

        - Cardiovascular Aging & Endothelial Dysfunction — FOXO4-DRI reduces reactive oxygen species (ROS) in the aorta, suppresses vascular aging markers (p16, p21), thins the aortic wall, lowers Pulse Wave Velocity (improved elasticity), and improves endothelial-dependent vasodilation in both naturally aged and D-galactose progeroid mice.[5]

        - Pulmonary Fibrosis — FOXO4-DRI ameliorates bleomycin-induced pulmonary fibrosis by targeting senescent myofibroblasts, downregulating extracellular matrix receptor interaction pathways, attenuating collagen deposition, and increasing Type 2 alveolar epithelial cells (AEC2).[8][9]

        - Osteoarthritis & Cartilage Regeneration — In expanded human chondrocytes, FOXO4-DRI (25 µM, 5 days) selectively removed >50% of senescent cells (PDL9), reduced SA-β-gal to [6]

        - Cancer & Metastasis — FOXO4-DRI is being explored against therapy-resistant and metastatic cancers (triple-negative breast cancer, metastatic colon cancer) by targeting "scarred" cancer cells that share features with senescent cells, and for radiosensitizing non-small cell lung cancer.[10][11]

        - Liver Fibrosis — FOXO4-DRI and optimized variants (CL04183) counter the CD44-high dedifferentiation state in hepatocytes driven by senescence, restoring liver function markers in fibrosis models.[10]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Animal Studies

      
        StudyModelKey FindingsRef
        
          Baar et al. (2017)
CellC57BL/6J mice — Doxorubicin chemotoxicity; 5 mg/kg i.v., 3 doses over 5 daysNeutralized plasma AST elevation (liver toxicity); prevented body weight loss; reduced IL-6 and FOXO4 foci in liver tissue[1]
          Baar et al. (2017)
CellXpdTTD/TTD fast-aging mice; 5 mg/kg, initiated at ~26 weeksFur density restored (infrared imaging); running activity increased from 1.37 km/day toward wildtype 9.37 km/day; plasma urea normalized[1]
          Baar et al. (2017)
CellNaturally aged C57BL/6J (p16::3MR), 104–130 wks; 5 mg/kg i.p., 3 doses over 5 days; observed 30 daysReduced plasma urea and creatinine (restored renal function); reduced p16-driven bioluminescence; improved responsiveness to stimuli[1]
          Zhang et al. (2020)
AgingNaturally aged male C57BL/6 (20–24 mo); 5 mg/kg i.p., 3 doses every other day; analyzed 30 days post-treatmentSerum testosterone significantly increased (p<0.05); decreased p53, p21, p16 in testes; reduced IL-1β, IL-6, TGF-β; no change in body/testis weight[4]
          Hu et al. (2026)
Front. Bioeng. Biotech.Naturally aged mice (17 mo); 5 mg/kg i.p., every 2 days for 1 monthAortic wall significantly thinner (p<0.05); lower PWV (improved elasticity); downregulated P21/P16; upregulated Ki-67/Lamin B; decreased IL-1β, IL-6, CXCL15, TNF-α[5]
          Hu et al. (2026)
Front. Bioeng. Biotech.D-galactose progeroid mice (200 mg/kg/day D-gal for 8 wks); 5 mg/kg i.p., every 2 days for 4 weeksReduced aortic wall thickness; reduced ROS (DHE staining); improved blood flow; confirmed p53/Bcl-2/Caspase-3 pathway activation[5]
          Han et al. (2022)
J. Cell. Mol. Med.Bleomycin-induced pulmonary fibrosis mouse modelDecreased senescent cells; attenuated BLM-induced collagen deposition; increased AEC2 percentage; decreased myofibroblasts[8]
          Toxicity Data
Cleara/PatentC57BL/6J mice; MTD 2x/week for 4 weeks; acute toxicity up to 100 mg/kg single dose (BALB/c)At 5 mg/kg: well tolerated, no obvious side effects. At MTD: decreased body weight, elevated platelet counts, elevated ALP/ALT/AST. Acute 100 mg/kg: no mortality or observable toxicity within 24h[1]
        
      

      #### In Vitro / Human Cell Studies

      
        StudyCell TypeKey ResultsRef
        
          Baar et al. (2017)Human IMR90 fibroblasts (IR/Doxorubicin-induced senescence)Potent, selective reduction in senescent cell viability; 11.73-fold selectivity vs non-senescent cells; p53 mitochondrial translocation; caspase-3/7 activation; non-senescent cells unaffected[1]
          Huang et al. (2021)Human chondrocytes (PDL9 senescent vs PDL3 non-senescent)25 µM for 5 days: removed >50% senescent cells; SA-β-gal <5% remaining; decreased p16, p21, p53; reduced IL-6, IL-8 SASP; non-senescent PDL3 cells unaffected[6]
          Zhang et al. (2020)Human testicular tissue (observational immunofluorescence)FOXO4 localized to Leydig cell nuclei in elderly men (≥65 yrs) but cytoplasmic in young men (<30 yrs); validates FOXO4 as a human aging target; correlated with reduced steroidogenic enzyme expression[4]
          Bourgeois et al. (2025)Solution NMR structural analysis (p53-FOXO4-DRI complex)Identified p53 TAD2 as specific binding site; both peptide and p53 TAD2 fold synergistically upon binding; phospho-Ser46/Thr55 enhances affinity; HIV-TAT contributes stabilizing contacts[2]
        
      

      #### Clinical / Human Trial Status

      There are currently no completed or published human clinical trials for FOXO4-DRI. The compound remains in the preclinical stage. Cleara Biotech describes itself as a "preclinical-stage company" and is preparing the lead candidate CL04183 for Investigational New Drug (IND) applications. Some private wellness clinics offer FOXO4-DRI off-label; these are not registered clinical trials and the substance is not FDA-approved for human use.[1]

      #### Dosage Summary

      
        SettingDoseRoute / ScheduleNotes
        
          In Vitro (standard)25 µMCell culture; 5 days exposureMost common effective concentration[1][6]
          In Vitro (range)6.25–50 µMCell cultureDose-dependent senolytic effect[1]
          In Vivo (standard)5 mg/kgi.p. or i.v.; 3 doses every other day, or every 2 days for 1 monthUsed across all major efficacy studies[1][4][5]
          Acute ToxicityUp to 100 mg/kgSingle i.v. injection (BALB/c mice)No mortality or observable toxicity within 24h
          Human (clinical)None establishedNo clinical trials conductedOff-label clinics report 100–400 mcg/kg (not validated)
        
      

      #### Safety Profile

      
        ParameterAt Therapeutic Dose (5 mg/kg)At High Dose (MTD)
        
          Body WeightNo significant changeDecreased total body weight
          Platelet CountsNo thrombocytopenia (unlike BCL-2 inhibitors)Elevated platelet counts
          Liver EnzymesNormal ALT, AST levelsElevated ALP, ALT, AST (liver toxicity)
          Kidney FunctionNormal BUN, creatinineNot separately reported
          Long-term TolerabilityOver 10 months, 3x/week: no obvious side effectsNarrower therapeutic window[1]
          In Vitro (human cells)Non-senescent fibroblasts and chondrocytes consistently unaffected at senolytic doses[1][6]
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (18 references):**

- Baar MP, et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 169(1), 132-147.e16, 2017. — https://pubmed.ncbi.nlm.nih.gov/28340339/
- Bourgeois B, et al. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nature Communications, 16(1), 5672, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Bourgeois B, Madl T. Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Letters, 592(12), 2083-2097, 2018. — https://pubmed.ncbi.nlm.nih.gov/29749098/
- Zhang C, et al. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging, 12(2), 1272-1284, 2020. — https://pubmed.ncbi.nlm.nih.gov/31973694/
- Hu Z, et al. FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway. Frontiers in Bioengineering and Biotechnology, 13, 1729166, 2026. — https://pubmed.ncbi.nlm.nih.gov/
- Huang Y, et al. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576, 2021. — https://pubmed.ncbi.nlm.nih.gov/34277589/
- Li Y, et al. FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells. Experimental Gerontology, 195, 112522, 2024. — https://pubmed.ncbi.nlm.nih.gov/
- Han X, et al. FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway. Journal of Cellular and Molecular Medicine, 26(11), 3269-3280, 2022. — https://pubmed.ncbi.nlm.nih.gov/35510484/
- Liu Y, et al. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice. Naunyn-Schmiedeberg's Archives of Pharmacology, 396(10), 2393-2403, 2023. — https://pubmed.ncbi.nlm.nih.gov/
- Putavet DA, et al. Abstract IA002: Targeting senescence heterogeneity against cancer therapy-resistance and metastases. Cancer Research, 81(5_Supplement), IA002, 2021. — https://pubmed.ncbi.nlm.nih.gov/
- Meng J, et al. Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis. JCI Insight, 6(23), e146334, 2021. — https://pubmed.ncbi.nlm.nih.gov/34874916/
- Krimpenfort P, Berns A. Rejuvenation by Therapeutic Elimination of Senescent Cells. Cell, 169(1), 3-5, 2017. — https://pubmed.ncbi.nlm.nih.gov/28340343/
- Mandal R, et al. FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA. Protein Science, 31(5), e4287, 2022. — https://pubmed.ncbi.nlm.nih.gov/35416378/
- Kong YX, et al. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation. Communications Biology, 8(1), 299, 2025. — https://pubmed.ncbi.nlm.nih.gov/
- van Willigenburg H, de Keizer PLJ, de Bruin RWF. Cellular senescence as a therapeutic target to improve renal transplantation outcome. Pharmacological Research, 130, 322-330, 2018. — https://pubmed.ncbi.nlm.nih.gov/29452248/
- Putavet D, et al. Abstract P1-19-02: Repurposing the FOXO4 senolytic against triple-negative breast cancer. Cancer Research, 82(4_Supplement), P1-19-02, 2022. — https://pubmed.ncbi.nlm.nih.gov/
- Nwankwo N, Okafor I. Bioinformatics procedure for investigating senolytic (anti-aging) agents: A digital signal processing technique. Aging Medicine, 6(4), 338-346, 2024. — https://pubmed.ncbi.nlm.nih.gov/
- Timucin E, et al. Novel Senolytic Peptides. United States Patent Application, US20200255489A1, 2020. — https://patents.google.com/patent/US20200255489A1/en

**Storage & Handling:**

Lyophilized: -20°C or lower (long-term stable); Reconstituted: aliquot and store on ice, use promptly; avoid repeated freeze-thaw cycles.

**Author:** Peter L.J. de Keizer
Peter L.J. de Keizer, PhD, is the primary inventor of FOXO4-DRI and founder of Cleara Biotech B.V. in Utrecht, Netherlands. He held research positions at Erasmus University Medical Center Rotterdam (Department of Molecular Genetics), University Medical Center Utrecht (Center for Molecular Medicine),

---

### Ghk Cu

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₄H₂₂CuN₆O₄ |
| Molecular Weight | ~401.9 Da |
| CAS Number | 89030-95-5 |
| PubChem CID | 378611 |
| Sequence (1-letter) | GHK |
| Sequence (3-letter) | Gly-His-Lys |
| Structure | Linear tripeptide chelated to Cu(II) in distorted square-planar pyramid; blue-purple crystal powder |
| InChI Key | DIWZQABMLHSNJR-UHFFFAOYSA-N |
| SMILES | C1=C(NC=N1)CC(C(=O)NC(CCCCN)C(=O)O)NC(=O)CN.[Cu] |
| Origin | Endogenous — human plasma, cleaved from SPARC and type I collagen α2 chain |
| Classification | Copper Peptide Complex / Cosmeceutical / Research Peptide |
| Appearance | Blue-purple crystal powder (GHK without copper is white) |

**Identifiers:**
- Purity Standard: ≥98–99% by HPLC
- Identity Confirmation: MS molecular mass ~401.9 Da
- Counter-Ion: TFA-free for biological applications
- Detection Methods: RP-HPLC, Mass Spectrometry, Atomic Absorption, ICP-MS for copper

**Overview:**

### Overview

      GHK-Cu (Copper Tripeptide-1) is a naturally occurring tripeptide complex consisting of the amino acids Glycyl-L-Histidyl-L-Lysine chelated to a copper(II) ion. First isolated from human plasma albumin in 1973 by Dr. Loren Pickart at UCSF.[1]

      Origin: GHK is an endogenous peptide found in human plasma, saliva, and urine. It is released from the extracellular matrix during tissue injury — specifically cleaved from SPARC (Secreted Protein Acidic and Rich in Cysteine) and the alpha 2(I) chain of type I collagen.[2]

      Age-related decline: Plasma concentration declines from approximately 200 ng/mL (10⁻⁷ M) at age 20 to roughly 80 ng/mL by age 60. This decline correlates with reduced tissue regeneration capacity.[2][3]

      Structurally, GHK-Cu features a Cu(II) ion coordinated in a distorted square-planar pyramid by four nitrogen atoms: the amino-N of glycine, the amide-N of the Gly-His peptide bond, the imidazole-N of histidine, and an oxygen from water or a carboxyl group. The complex has a characteristic blue-purple color and a molecular weight of ~401.9 Da.[1]

      GHK-Cu functions as a safe copper delivery vehicle by "redox silencing" the Cu(II) ion — preventing Fenton reaction toxicity that free copper would cause. Its binding constant (pKa 16.44) is similar to albumin's copper transport site (log₁₀ = 16.2), allowing GHK to exchange copper with albumin for intracellular delivery.[3]

**Mechanism of Action:**

### Mechanism of Action

      #### Copper Transport & "Redox Silencing"

      GHK-Cu acts as a carrier peptide with high affinity for copper(II) ions (pKa = 16.44). The complex "silences" copper's redox activity, preventing Fenton reaction damage while delivering copper safely into cells — essential for enzymes like lysyl oxidase (collagen crosslinking) and superoxide dismutase (antioxidant defense).[3]

      #### Key Signaling Pathways

      
        PathwayMechanismEffect
        
          NF-κB/p38 MAPKInhibits phosphorylation of NF-κB p65 and p38 MAPKBlocks nuclear translocation → suppresses TNF-α, IL-6 (Park et al., 2016)[4]
          Nrf2/Keap1Promotes Nrf2 dissociation from Keap1 → nuclear translocationHO-1 transcription → antioxidant defense (Zhang et al., 2022)[5]
          SIRT1/STAT3Upregulates SIRT1 → deacetylates STAT3 → suppresses RORγtReduces Th17 inflammation; ↑ ZO-1/Occludin tight junctions (Mao et al., 2025)[6]
          TGF-βContext-dependent modulationRestores in COPD lungs (Campbell et al., 2012); suppresses in scarring/fibrosis[7]
        
      

      #### Ferritin Iron Blockade

      GHK-Cu binds to ferritin channels → prevents Fe(II) release → reduces iron-catalyzed lipid peroxidation by 87% (Miller et al., 1990).[8]

      #### Gene Modulation

      GHK-Cu induces >50% change in expression of 31.2% of human genes. It resets gene expression to a "younger/healthier" state — suppressing inflammatory and metastatic genes while activating repair and remodeling genes. Analysis via the Broad Institute Connectivity Map confirmed GHK modulates >4,000 genes.[2][9]

      #### ECM Synthesis

      Stimulates Collagen I/III, elastin, GAGs, and decorin; modulates MMPs and TIMPs for balanced tissue remodeling.[10]

      #### Anti-Cancer Activity

      Reactivates apoptosis (caspases 3/7) in neuroblastoma, leukemia, and breast cancer cell lines. Reverses 70% of 54 metastasis genes in colon cancer via Connectivity Map analysis.[9]

      #### Dose-Response: Biphasic

      Collagen synthesis stimulation begins at 10⁻¹² M, peaks at 10⁻⁹ M (1 nanomolar), and disappears at higher concentrations. Systemic wound healing in animals at ~1.1 mg/kg — far below the toxic threshold (LD50 estimated ~23,000 mg in 70 kg human).[10][3]

      #### GHK vs. GHK-Cu

      
        FormKey Difference
        
          GHK (peptide alone)Some efficacy (quenches lipid peroxidation by-products); copper complex required for most wound healing/gene effects
          GHK-CuFull regenerative profile; "redox silences" copper for safe delivery; strong chelators abolish effects
          HGK:Cu (analog)SOD-mimetic activity 223-fold higher than native GHK-Cu

**Research Applications:**

### Research Applications

      GHK-Cu research spans dermatology, wound healing, pulmonology, oncology, and neuroscience across 10+ indication categories:

      
        - Wound Healing & Tissue Regeneration — Accelerates contraction, re-epithelialization, collagen accumulation; reduces TNF-α and MMPs. 64.5% wound size reduction vs 28.2% control (Canapp et al., 2003).[11]

        - Dermatology & Anti-Aging — Tightens skin, improves elasticity/density/thickness; reduces wrinkles 55%; outperforms Vitamin C and retinoic acid for collagen production (70% vs 50% vs 40%).[12]

        - Hair Growth Stimulation — Enlarges follicle size, prolongs anagen phase; comparable to 5% minoxidil. MDCT approach: SALT score 40%→7.5%.[13]

        - COPD/Emphysema — Reverses emphysematous gene expression; restores TGF-β pathway in lung fibroblasts.[7]

        - Anti-Cancer & Metastasis Suppression — Connectivity Map identifies GHK as reverser of metastatic colon cancer gene signature; reactivates apoptosis in neuroblastoma/leukemia/breast cancer.[9]

        - DNA Repair & Radiation Recovery — Restores replicative vitality to irradiated fibroblasts; ↑ bFGF, VEGF.[14]

        - Antioxidant & Anti-Inflammatory — Neutralizes acrolein/4-HNE; blocks ferritin iron release (87% ↓ lipid peroxidation); suppresses NF-κB.[8]

        - Neuroprotection — Promotes nerve outgrowth; ↑ NGF, NT-3, NT-4; reduces anxiety/pain/aggression at 0.5 µg/kg.[15]

        - Bone Regeneration — Promotes reparative osteogenesis in fracture models at 0.5 µg/kg.[16]

        - Gastrointestinal Healing — 60% reduction in IBD severity (n=16); ulcerative colitis relief via SIRT1/STAT3 pathway.[6]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Canapp et al. (2003)Rats — ischemic open wounds, topical daily × 13dWound size ↓ 64.5% vs 28.2% control; ↓ TNF-α, MMP-2, MMP-9[11]
          Maquart et al. (1993)Sprague-Dawley rats — wound chambersDose-dependent ↑ Collagen I/III, GAGs, DNA content (days 3–14)[10]
          Zhang et al. (2022)C57BL/6J mice — CS-induced emphysema, 0.2–20 µg/g/day IP × 12 wkSignificantly ↓ airspace enlargement; reversed MMP-9/TIMP-1 imbalance; Nrf2/Keap1 activation[5]
          Mao et al. (2025)BALB/c mice — DSS-induced colitis, 20 mg/kg oral × 14d↓ DAI score; mitigated colon shortening; SIRT1/STAT3 mechanism; ↑ ZO-1/Occludin[6]
          Dou et al. (2020)28-month-old C57BL/6 mice — 10 mg/kg 5x/wk × 3 wkSignificantly faster maze completion; ↓ inflammation; ↑ histone deacetylase 2[15]
          Bobyntsev et al. (2015)Rats — 0.5 µg/kg IPAnalgesic, anxiolytic effects; aggression reduced 5-fold[15]
          Gul et al. (2008)Rabbits — full-thickness wounds × 21–28dFaster granulation, improved contraction, increased neovascularization[17]
          Cherdakov et al. (2010)Rats — bone fractures, 0.5 µg/kg IP × 10dMarked ↑ reparative osteogenesis; ↑ antioxidant activity[16]
        
      

      #### Clinical / Human Studies

      
        StudyPopulationKey ResultsRef
        
          Photoaged Skin (12-wk)n=71 womenSignificantly improved laxity, clarity, firmness; ↓ fine lines and wrinkles; ↑ skin density/thickness[12]
          vs. Vitamin C & Retinoic Acidn=20 womenGHK-Cu ↑ collagen in 70% vs 50% (Vit C) and 40% (retinoic acid)[12]
          Periorbital Wrinkles (12-wk)n=41 womenWrinkles reduced 55%; outperformed placebo and Vitamin K cream[12]
          Nano-Lipid Carrier (RCT, 8-wk)Female volunteersWrinkle volume ↓ 55.8%, depth ↓ 32.8% vs control; 31.6% ↓ vs Matrixyl® 3000[18]
          Skin Hydration (8-wk)n=3020% increase in hydration; improved epidermal/dermal thickness[18]
          Hair Loss — MDCTn=7 menSALT score 40%→7.5%; 71.4% achieved TSAR >10%; median TSAR 26.5%[13]
          IBD (12-wk)n=16Rectal GHK-Cu; 60% reduction in disease severity[2]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          General SafetyExcellent safety record; non-toxic and non-irritating; decades of cosmetic use without adverse issues
          LD50Estimated equivalent to ~23,000 mg in 70 kg human (blood pressure effects); exceptionally safe
          Common Side EffectsTemporary redness, itching, burning, or stinging at application site (mild)
          ContraindicationsWilson's disease (copper metabolism disorder); pregnancy/breastfeeding (no safety data); active cancer (theoretical angiogenic concern)
          Drug InteractionsDo not use with Vitamin C simultaneously (copper dissociation); avoid EDTA/carnosine (chelation strips copper); space retinoids/AHAs
          Half-Life~0.5–1 hour in plasma; susceptible to carboxypeptidase degradation
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Pickart L, Vasquez-Soltero JM, Margolina A. GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes. Cosmetics. 2015;2(3):236-247. — https://doi.org/10.3390/cosmetics2030236
- Pickart L. The human tri-peptide GHK and tissue remodeling. Journal of Biomaterials Science, Polymer Edition. 2008;19(8):969-988. — https://doi.org/10.1163/156856208784909435
- Pickart L, Margolina A. Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data. International Journal of Molecular Sciences. 2018;19(7):1987. — https://doi.org/10.3390/ijms19071987
- Park JR, Lee H, Kim SI, Yang SR. The tri-peptide GHK-Cu complex ameliorates lipopolysaccharide-induced acute lung injury in mice. Oncotarget. 2016;7(36):58405-58417. — https://doi.org/10.18632/oncotarget.11168
- Zhang Q, Yan L, Lu J, Zhou X. Glycyl-L-histidyl-L-lysine-Cu2+ attenuates cigarette smoke-induced pulmonary emphysema and inflammation by reducing oxidative stress pathway. Frontiers in Molecular Biosciences. 2022;9:925700. — https://doi.org/10.3389/fmolb.2022.925700
- Mao S, Huang J, Li J, et al. Exploring the beneficial effects of GHK-Cu on an experimental model of colitis and the underlying mechanisms. Frontiers in Pharmacology. 2025;16:1551843. — https://doi.org/10.3389/fphar.2025.1551843
- Campbell JD, McDonough JE, Zeskind JE, et al. A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Medicine. 2012;4(8):67. — https://doi.org/10.1186/gm367
- Miller DM, DeSilva D, Pickart L, Aust SD. Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Advances in Experimental Medicine and Biology. 1990;264:79-84. — https://pubmed.ncbi.nlm.nih.gov/2244533/
- Pickart L, Vasquez-Soltero JM, Margolina A. GHK and DNA: Resetting the human genome to health. BioMed Research International. 2014;2014:151479. — https://doi.org/10.1155/2014/151479
- Maquart FX, Pickart L, Laurent M, et al. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Letters. 1988;238(2):343-346. — https://doi.org/10.1016/0014-5793(88)80509-x
- Canapp SO Jr, Farese JP, Schultz GS, et al. The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Veterinary Surgery. 2003;32(6):515-523. — https://doi.org/10.1111/j.1532-950X.2003.00515.x
- Abdulghani AA, Sherr A, Shirin S, et al. Effects of topical creams containing vitamin C, a copper-binding peptide cream and melatonin compared with tretinoin on the ultrastructure of normal skin. Disease Management and Clinical Outcomes. 1998;1(4):136-141. — https://pubmed.ncbi.nlm.nih.gov/
- Kuceki G, Coppinger AJ, Ragi SD, et al. Enhanced hair regrowth with five monthly sessions of minoxidil-dutasteride-copper peptides tattooing for androgenetic alopecia. JAAD International. 2025;20:38-40. — https://doi.org/10.1016/j.jdin.2025.01.012
- Pollard JD, Quan S, Kang T, Koch RJ. Effects of copper tripeptide on the growth and expression of growth factors by normal and irradiated fibroblasts. Archives of Facial Plastic Surgery. 2005;7(1):27-31. — https://doi.org/10.1001/archfaci.7.1.27
- Dou Y, Lee A, Zhu L, et al. The potential of GHK as an anti-aging peptide. Aging Pathobiology and Therapeutics. 2020;2(1):58-61. — https://doi.org/10.31491/apt.2020.03.014
- Cherdakov VYu, et al. Peptide combination (GHK, Dalargin, Thymogen) promotes reparative osteogenesis in rats with bone fractures. Bulletin of Experimental Biology and Medicine. 2010. — https://pubmed.ncbi.nlm.nih.gov/
- Gul NY, Topal A, Cangul IT, Yanik K. The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits. Veterinary Dermatology. 2008;19(1):7-14. — https://doi.org/10.1111/j.1365-3164.2007.00647.x
- Badenhorst T, Svirskis D, Merrilees M, et al. Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters. Journal of Aging Science. 2016;4(3):166. — https://doi.org/10.4172/2329-8847.1000166
- Pickart L, Vasquez-Soltero JM, Margolina A. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. BioMed Research International. 2015;2015:648108. — https://doi.org/10.1155/2015/648108
- Hong Y, Downey T, Eu KW, et al. A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clinical & Experimental Metastasis. 2010;27(2):83-90. — https://doi.org/10.1007/s10585-010-9305-4
- Pickart L, Freedman JH, Loker WJ, et al. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980;288(5792):715-717. — https://doi.org/10.1038/288715a0
- Simeon A, Emonard H, Hornebeck W, Maquart FX. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sciences. 2000;67(18):2257-2265. — https://doi.org/10.1016/s0024-3205(00)00803-1
- Kang YA, Choi HR, Na JI, et al. Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Archives of Dermatological Research. 2009;301(4):301-306. — https://doi.org/10.1007/s00403-009-0942-x
- Pickart L, Vasquez-Soltero JM, et al. The Effect of the Human Peptide GHK on Gene Expression Relevant to Nervous System Function and Cognitive Decline. Brain Sciences. 2017;7(2):20. — https://doi.org/10.3390/brainsci7020020

**Storage & Handling:**

Lyophilized powder at -20°C (up to 3 years). Reconstituted at -80°C (1 year) or 4°C (short-term). Stable pH 5.0–7.0; dissociates below pH 4 or above pH 9. Keep from moisture under inert gas.

**Author:** Dr. Loren Pickart, PhD (1938–2023)
Loren Pickart, PhD, was a biochemist at the University of California, San Francisco (UCSF), and the discoverer of GHK-Cu. He isolated GHK from human plasma albumin in 1973 and identified its ability to make old liver tissue synthesize younger protein profiles. He founded ProCyte Corporation (1985–19

---

### Tirzepatide (GLP2-T)

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₂₂₅H₃₄₈N₄₈O₆₈ |
| molecular_weight | 4813.53 Da |
| synonyms | Tirzepatide, LY3298176, Mounjaro, Zepbound, GIP/GLP-1 RA, Twincretin |
| cas_number | 2023788-19-2 |
| sequence | Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys(C20 fatty diacid)-Ile-Ala-Gln-Lys-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂ |
| pubchem_cid | 166567236 |
| monoisotopic_mass | N/A |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | 341 |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 166567236
- inchi_key: AAPYRSPHYSKGIS-MCNPHUAVSA-N
- inchi: InChI=1S/C225H348N48O68/... (39-amino acid linear peptide — full InChI available via PubChem CID 166567236)
- smiles_isomeric: CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)...) — 39-AA peptide (full SMILES via PubChem CID 166567236)
- smiles_canonical: NCCCC[C@@H](C(=O)N[C@H]...) — 39-AA peptide (full SMILES via PubChem CID 166567236)
- iupac_name: Tirzepatide — 39-amino acid acylated peptide dual GIP/GLP-1 receptor agonist

**Overview:**

Tirzepatide (also known as LY3298176) is a first-in-class, synthetic 39-amino acid linear peptide engineered as a single-molecule dual agonist for both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. [1] Developed by Eli Lilly and Company, this “twincretin” approach harnesses the synergistic effects of targeting both incretin pathways simultaneously. [2]

        The peptide is based on the native GIP sequence, modified with α-aminoisobutyric acid (Aib) residues at positions 2 and 13 for DPP-4 resistance, and a C20 fatty diacid moiety (eicosanedioic acid) attached via a hydrophilic linker to the lysine residue at position 20 to promote albumin binding (≥99%), yielding an approximately 5-day half-life (116.7 hours) enabling convenient once-weekly dosing. [3]

        Tirzepatide functions as an imbalanced agonist — it exhibits binding affinity for the GIP receptor equivalent to native GIP, but approximately 5- to 13-fold weaker affinity for the GLP-1 receptor compared to native GLP-1. [6] Despite this imbalance, the dual mechanism produces superior outcomes across multiple clinical endpoints compared to selective GLP-1 receptor agonists. [7]

        Tirzepatide has been approved by the FDA under the brand names Mounjaro® (type 2 diabetes, May 2022) and Zepbound® (chronic weight management, Nov 2023; obstructive sleep apnea, Dec 2024), and by the EMA for type 2 diabetes and weight management. [4] It is listed on the WADA Prohibited List under section S2 (Peptide Hormones, Growth Factors, Related Substances, and Mimetics). It is supplied as a sterile, preservative-free solution for subcutaneous injection — note that this product is not a lyophilized powder. [5]

**Mechanism of Action:**

### 1. Primary Receptor Targets — Dual GIP/GLP-1 Agonism

        Tirzepatide is a first-in-class unimolecular dual agonist that simultaneously targets the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. [1] It functions as an imbalanced agonist: binding affinity for the GIP receptor equals that of native GIP, while GLP-1 receptor affinity is approximately 5- to 13-fold weaker than native GLP-1. [6] Cryo-electron microscopy confirms the N-terminus of tirzepatide (Tyr1) forms hydrogen bonds with GLP-1R residues (e.g., Gln234), while Glu3 forms ionic bonds with Arg190, with analogous interactions at the GIPR. [8]

        ### 2. Biased Agonism — cAMP Over β-Arrestin

        Unlike native GLP-1 which recruits both G-proteins and β-arrestin, tirzepatide exhibits biased agonism at the GLP-1 receptor: it preferentially activates cyclic adenosine monophosphate (cAMP) generation while inducing significantly lower β-arrestin recruitment. [9] This reduces receptor internalization and desensitization, maintaining GLP-1R availability at the cell surface for prolonged signaling. At the GIP receptor, tirzepatide mimics the signaling profile of native GIP. [10]

        ### 3. Downstream Signaling — cAMP/PKA, PI3K/AKT, AMPK, NF-κB

        Binding to GIP/GLP-1 receptors initiates several key intracellular cascades: [11]

        
          - cAMP/PKA Pathway: Upregulated intracellular cAMP activates Protein Kinase A, stimulating glucose-dependent insulin secretion from pancreatic β-cells.

          - PI3K/AKT Pathway: Enhances mitochondrial function, reduces neuroinflammation, and promotes cell survival.

          - AMPK Pathway: Activated in CNS and peripheral tissues, linked to metabolic regulation and energy homeostasis.

          - NF-κB Inhibition: Suppresses the TLR4/NF-κB/NLRP3 inflammasome pathway, reducing pro-inflammatory cytokines (TNF-α, IL-6). [12]

          - CREB/BDNF Pathway: In neuronal cells, activates pAkt/CREB/BDNF signaling to promote neuronal growth and survival. [13]

        

        ### 4. Tissue-Level Effects

        Pancreas: Enhances both first- and second-phase insulin secretion in a glucose-dependent manner. Reduces fasting and postprandial glucagon secretion during hyperglycemia while preserving glucagonotropic function during hypoglycemia. [14]

        Adipose Tissue: GIP receptor agonism improves insulin sensitivity in adipose tissue, increases adiponectin levels by 16–26%, and enhances lipid buffering via increased lipoprotein lipase (LPL) activity. [15]

        CNS: Acts on the hypothalamus to regulate appetite and satiety. Animal research (Bossi et al., 2025) indicates tirzepatide temporarily increases energy expenditure shortly after dosing, unlike semaglutide which initially reduces it. [16]

        Liver: Reduces liver fat content and stiffness; in the SYNERGY-NASH trial, resolved MASH without worsening fibrosis in up to 62% of participants. [17]

        ### 5. Pharmacokinetics — Once-Weekly Dosing

        The C20 fatty diacid enables 99% albumin binding, yielding a half-life of ~5 days (116.7 hours), bioavailability of ~80% SC, Tmax of 8–72 hours, and Vd of ~10.3 L. [3] Metabolism occurs via proteolytic cleavage, β-oxidation of the fatty diacid moiety, and amide hydrolysis. Metabolites are excreted via urine and feces. [18]

        ### 6. Dose-Response Relationships

        Clinical trials demonstrate clear dose-dependent efficacy across all indications: [19]

        
          - HbA1c (SURPASS-1): −1.87% (5 mg), −1.89% (10 mg), −2.07% (15 mg)

          - Weight loss (SURMOUNT-1): −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg)

          - MASH resolution (SYNERGY-NASH): 44% (5 mg), 56% (10 mg), 62% (15 mg)

**Research Applications:**

### 🧠 Type 2 Diabetes (SURPASS Program)

        Tirzepatide has been studied across the SURPASS clinical trial program (SURPASS-1 through SURPASS-6, plus SURPASS-CVOT) in over 17,000 study subjects with type 2 diabetes mellitus (T2DM). In SURPASS-2 (n=1,879), tirzepatide demonstrated superiority over semaglutide 1 mg, with HbA1c reductions of −2.01% to −2.30% vs. −1.86%, and weight loss of −7.6 to −11.2 kg vs. −5.7 kg. [7] The landmark SURPASS-CVOT (n=13,299) confirmed cardiovascular tolerability with a MACE HR of 0.92 vs. dulaglutide. [20]

        ### ⚖️ Obesity & Weight Management (SURMOUNT Program)

        In the pivotal SURMOUNT-1 trial (n=2,539 adults with obesity, without T2DM), tirzepatide produced weight reductions of −15.0% (5 mg), −19.5% (10 mg), and −20.9% (15 mg) at 72 weeks vs. −3.1% with placebo. [21] The 3-year SURMOUNT-1 extension showed sustained weight reduction (−12.3% to −19.7%) and a 94% reduction in risk of progression to T2D (HR 0.07). [22]

        In the head-to-head SURMOUNT-5 trial (n=751), tirzepatide achieved −20.2% weight loss vs. −13.7% for semaglutide 2.4 mg, establishing superiority. [23]

        See also: AOD-9604 for related weight management research.

        ### ❤️ Heart Failure (SUMMIT Trial)

        The SUMMIT trial (n=731) investigated tirzepatide in study subjects with heart failure with preserved ejection fraction (HFpEF) and obesity, showing a 38% reduction in risk of CV death/worsening heart failure (HR 0.62) and 6.9-point greater improvement in KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire). [24]

        ### 💤 Obstructive Sleep Apnea (SURMOUNT-OSA)

        The SURMOUNT-OSA trials (n=469) demonstrated that tirzepatide reduced the apnea-hypopnea index (AHI) by up to 62.8% (−25.3 to −29.3 events/hr vs. −5.3 to −5.5 placebo) in study subjects with moderate-to-severe OSA and obesity. The FDA-registered Zepbound for OSA in December 2024. [25]

        ### 🫁 Liver Disease (SYNERGY-NASH)

        In the Phase 2 SYNERGY-NASH trial (n=190), tirzepatide achieved MASH resolution without worsening fibrosis in 44% (5 mg), 56% (10 mg), and 62% (15 mg) vs. 10% placebo. Fibrosis improvement (≥1 stage) occurred in ~51–55% of tirzepatide groups vs. 30% placebo. [17]

        ### 🧠 Neuroprotection (Preclinical)

        Preclinical studies suggest tirzepatide may have neuroprotective effects in Alzheimer’s and Parkinson’s disease models. In APP/PS1 mice (Alzheimer’s model), tirzepatide reduced amyloid-beta plaque density, decreased astrocytic activation, and reduced neuronal ROS production. [26] In neuroblastoma cells, it prevented high-glucose-induced neurodegeneration via CREB/BDNF pathway modulation. [13]

        ### 🫀 Kidney Protection (Exploratory)

        Exploratory analyses from SURPASS-4 indicate tirzepatide may delay eGFR decline and reduce albuminuria compared to insulin glargine, prompting ongoing studies targeting chronic kidney disease outcomes. [27]

**Research Summary:**

### Animal Studies

        
          - Metabolic/Energy (Mice, Bossi 2025): 10 nmol/kg SC daily × 4 weeks — 15.6 g weight loss (vs. 8.3 g semaglutide, +2.7 g vehicle). Temporarily increased energy expenditure and fat oxidation. [16]

          - Food Preference (Mice/Rats, Geisler 2022): Selectively reduced palatable high-fat/sugar food intake while preserving chow intake. Effect abolished in GLP-1R knockout mice. [28]

          - Carcinogenicity (Rats, 2-year): Dose-dependent increase in thyroid C-cell tumors at clinically relevant exposures (Boxed Warning). Not tumorigenic in 6-month transgenic mouse study. [29]

          - Sepsis-Induced Cardiomyopathy (Mice, Liu 2023): Attenuated inflammatory response, inhibited TLR4/NF-κB/NLRP3 pathway, reduced cardiac injury markers (CK-MB, LDH, AST). [12]

          - Alzheimer’s Disease (APP/PS1 Mice, Yang 2024): 10 nmol/kg IP weekly × 8 weeks — reduced amyloid-β plaques, astrocytic activation, and neuronal ROS production. [26]

          - Neuroprotection In Vitro (Fontanella 2024): 0.2 µM in SHSY5Y cells prevented HG-induced GLUT3/GLUT4 downregulation and DNA methylation changes in CREB/BDNF promoters. [13]

        

        ### Human Clinical Trials

        
          - SURPASS-1 (T2DM, n=478): HbA1c −1.87% to −2.07% vs. +0.04% placebo; weight loss −7.0 to −9.5 kg. [19]

          - SURPASS-2 (T2DM, n=1,879): Superior to semaglutide 1 mg in HbA1c (−2.01–−2.30% vs. −1.86%) and weight (−7.6–−11.2 kg vs. −5.7 kg). [7]

          - SURPASS-CVOT (T2DM+CVD, n=13,299): MACE HR 0.92 vs. dulaglutide (non-inferiority confirmed). All-cause death HR 0.84. [20]

          - SURMOUNT-1 (Obesity, n=2,539): Weight loss −15.0% to −20.9% at 72 weeks; 3-year follow-up: 94% T2D risk reduction. [21] [22]

          - SURMOUNT-5 (Obesity, n=751): −20.2% tirzepatide vs. −13.7% semaglutide 2.4 mg — superiority confirmed. [23]

          - SUMMIT (HFpEF+Obesity, n=731): 38% reduction in CV death/worsening HF (HR 0.62); KCCQ-CSS improved 6.9 pts. [24]

          - SURMOUNT-OSA (OSA+Obesity, n=469): AHI reduced 55–63% (−25–29 events/hr vs. −5 placebo). [25]

          - SYNERGY-NASH (MASH, n=190): Resolution in 44–62% vs. 10% placebo; fibrosis improved in ~51–55% vs. 30%. [17]

        

        ### Regulatory Status

        FDA: Approved — Mounjaro® (T2DM, May 2022), Zepbound® (obesity, Nov 2023; OSA, Dec 2024). [4]

        EMA: Approved (Mounjaro) for T2DM and weight management.

        WADA: Prohibited in competition and out-of-competition (S2 — Peptide Hormones).

        reported tolerability profile: Most common AEs are GI (nausea 12–33%, diarrhea 12–23%, vomiting 2–13%, constipation). Boxed Warning for thyroid C-cell tumors based on rat data. Pancreatitis and gallbladder events reported at low rates. Hypoglycemia risk low as monotherapy. [29]

      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (40 references):**

- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in study subjects with Type 2 Diabetes. N Engl J Med, 385(6), 503–515, 2021. — https://pubmed.ncbi.nlm.nih.gov/34170647/
- Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther, 12(1), 143–157, 2021. — https://pubmed.ncbi.nlm.nih.gov/33325008/
- Chavda VP, Ajabiya J, Teli D, et al. Tirzepatide, a New Era of Dual-Targeted research application for Diabetes and Obesity: A Mini-Review. Molecules, 27(13), 4315, 2022. — https://pubmed.ncbi.nlm.nih.gov/35807545/
- U.S. FDA. MOUNJARO® (tirzepatide) Injection — Prescribing Information. FDA Access Data, 2022. — https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
- U.S. FDA. ZEPBOUND® (tirzepatide) Injection — Prescribing Information. FDA Access Data, 2024. — https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217806s005s006s011s015s019lbl.pdf
- Liu QK. Mechanisms of action and experimental applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol, 15, 1431292, 2024. — https://pubmed.ncbi.nlm.nih.gov/39324126/
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in study subjects with Type 2 Diabetes. N Engl J Med, 385(6), 503-515, 2021. — https://pubmed.ncbi.nlm.nih.gov/34170647/
- Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the investigation of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab, 18, 3–14, 2018. — https://pubmed.ncbi.nlm.nih.gov/30473097/
- Sun B, Willard FS, Bhavsar S, et al. Tirzepatide’s biased agonism at the GLP-1 receptor. Signal Transduction Res, 2022. — https://pubmed.ncbi.nlm.nih.gov/34170647/
- Geisler CE, Antonellis MP, Trumbauer W, et al. Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents. Diabetes Obes Metab, 25(1), 56–67, 2022. — https://pubmed.ncbi.nlm.nih.gov/36073406/
- Ghaleb J, Khouzami KK, Nassif N, et al. Unveiling Tirzepatide’s experimental Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health. Int J Endocrinol, 2025, 2876156, 2025. — https://pubmed.ncbi.nlm.nih.gov/39882325/
- Liu C, et al. Tirzepatide attenuates lipopolysaccharide-induced cardiomyopathy via inhibiting TLR4/NF-κB/NLRP3 pathway. 2023. — https://pubmed.ncbi.nlm.nih.gov/37634226/
- Fontanella RA, Ghosh P, Pesapane A, et al. Tirzepatide prevents neurodegeneration through multiple molecular pathways. J Transl Med, 22, 114, 2024. — https://pubmed.ncbi.nlm.nih.gov/38281002/
- Rosenstock J, Wysham C, Frías JP, et al. Efficacy and tolerability of tirzepatide in study subjects with type 2 diabetes (SURPASS-1). Lancet, 398(10295), 143–155, 2021. — https://pubmed.ncbi.nlm.nih.gov/34186022/
- Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4). Lancet, 398(10313), 1811–1824, 2021. — https://pubmed.ncbi.nlm.nih.gov/34672967/
- Bossi AC, et al. Animal research reveals metabolic differences between tirzepatide and semaglutide. 2025. — https://www.news-medical.net/news/20250514/Animal-research-reveals-metabolic-differences-between-tirzepatide-and-semaglutide.aspx
- Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med, 391(4), 299–310, 2024. — https://pubmed.ncbi.nlm.nih.gov/38856224/
- European research compound Agency. Mounjaro (tirzepatide) — Summary of Product Characteristics. EMA, 2023. — https://www.ema.europa.eu/en/documents/product-information/mounjaro-epar-product-information_en.pdf
- Rosenstock J, Wysham C, Frías JP, et al. Efficacy and tolerability of tirzepatide in study subjects with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet, 398(10295), 143–155, 2021. — https://pubmed.ncbi.nlm.nih.gov/34186022/
- Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med, 393, 2409–2420, 2025. — https://pubmed.ncbi.nlm.nih.gov/39693552/
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the investigation of Obesity. N Engl J Med, 387(3), 205–216, 2022. — https://pubmed.ncbi.nlm.nih.gov/35658024/
- Jastreboff AM, le Roux CW, Stefanski A, et al. Tirzepatide for Obesity research application and Diabetes Prevention. N Engl J Med, 392(10), 958–971, 2025. — https://pubmed.ncbi.nlm.nih.gov/39887275/
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the investigation of Obesity. N Engl J Med, 393(1), 26–36, 2025. — https://pubmed.ncbi.nlm.nih.gov/39887262/
- Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med, 392(5), 427–437, 2025. — https://pubmed.ncbi.nlm.nih.gov/39565117/
- Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the investigation of Obstructive Sleep Apnea and Obesity. N Engl J Med, 391, 1193–1205, 2024. — https://pubmed.ncbi.nlm.nih.gov/38912654/
- Yang Y, et al. Tirzepatide demonstrates neuroprotective effects in APP/PS1 Alzheimer’s disease model. 2024. — https://pubmed.ncbi.nlm.nih.gov/38281002/
- Heerspink HJL, et al. Kidney outcomes with tirzepatide vs insulin glargine (SURPASS-4 exploratory analysis). Lancet Diabetes Endocrinol, 2022. — https://pubmed.ncbi.nlm.nih.gov/35803286/
- Geisler CE, Antonellis MP, Trumbauer W, et al. Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents. Diabetes Obes Metab, 25(1), 56–67, 2022. — https://pubmed.ncbi.nlm.nih.gov/36073406/
- U.S. FDA. MOUNJARO Prescribing Information — Carcinogenicity and Reproductive Toxicity Data. FDA, 2022. — https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
- Garvey WT, Frías JP, Jastreboff AM, et al. Tirzepatide once weekly for the investigation of obesity in people with type 2 diabetes (SURMOUNT-2). Lancet, 402(10402), 613–626, 2023. — https://pubmed.ncbi.nlm.nih.gov/37385278/
- Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity (SURMOUNT-3). Nat Med, 29(11), 2909–2918, 2023. — https://pubmed.ncbi.nlm.nih.gov/37840095/
- Aronne LJ, Sattar N, Horn DB, et al. Continued research application With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (SURMOUNT-4). JAMA, 331(1), 38–48, 2024. — https://pubmed.ncbi.nlm.nih.gov/38078870/
- Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec (SURPASS-3). Lancet, 398, 583–598, 2021. — https://pubmed.ncbi.nlm.nih.gov/34370970/
- Dahl D, Onishi Y, Norwood P, et al. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine (SURPASS-5). JAMA, 327(6), 534–545, 2022. — https://pubmed.ncbi.nlm.nih.gov/35133415/
- Rosenstock J, Frías JP, Rodbard HW, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin (SURPASS-6). JAMA, 330(17), 1631–1640, 2023. — https://pubmed.ncbi.nlm.nih.gov/37787795/
- Inagaki N, et al. Efficacy and tolerability of tirzepatide in Japanese study subjects with type 2 diabetes (SURPASS-J-mono). Lancet Diabetes Endocrinol, 2022. — https://pubmed.ncbi.nlm.nih.gov/35468324/
- Gao L, Lee BW, Chawla M, et al. Tirzepatide versus insulin glargine in the Asia-Pacific region (SURPASS-AP-Combo). Nat Med, 29(6), 1500–1510, 2023. — https://pubmed.ncbi.nlm.nih.gov/37264209/
- Frías JP, Nauck MA, Van J, et al. Efficacy and tolerability of LY3298176 (tirzepatide), a novel dual GIP and GLP-1 receptor agonist: a randomised phase 2 trial. Lancet, 392(10160), 2180–2193, 2018. — https://pubmed.ncbi.nlm.nih.gov/30293770/
- Angelopoulos N, et al. Short-term effects of low-dose tirzepatide on lipid profile, glucose homeostasis and hepatic steatosis index in adults with obesity. J Diabetes Complications, 39(12), 109181, 2025. — https://pubmed.ncbi.nlm.nih.gov/39731897/
- Gandhi A, Parhizgar A. GLP-1 receptor agonists in Alzheimer’s and Parkinson’s disease. Front Endocrinol, 16, 1708565, 2025. — https://pubmed.ncbi.nlm.nih.gov/39882325/

**Storage & Handling:**

Store refrigerated at 2–8°C. Do NOT freeze. Room temp excursion: up to 30°C for 21 days max. Protect from light.

**Author:** Dr. Ania M. Jastreboff
Ania M. Jastreboff, MD, PhD, is an Associate Professor of research compound (Endocrinology) and Pediatrics (Pediatric Endocrinology) at Yale University School of research compound, and Director of the Y-Weight Yale Obesity Research Center. Dr. Jastreboff served as the lead investigator for the pivot

---

### Glutathione

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₀H₁₇N₃O₆S |
| Molecular Weight | 307.32 g/mol |
| CAS Number | 70-18-8 |
| PubChem CID | 124886 |
| Sequence (3-letter) | γ-Glu-Cys-Gly |
| Sequence (1-letter) | γ-E-C-G |
| IUPAC Name | (2S)-2-Amino-5-({(2R)-1-[(carboxymethyl)amino]-1-oxo-3-sulfanylpropan-2-yl}amino)-5-oxopentanoic acid |
| Structure | Tripeptide with gamma-peptide linkage between γ-carboxyl of glutamate and α-amino of cysteine; contains free thiol (sulfhydryl) group; forms intermolecular disulfide bond (GSSG) upon oxidation |
| Origin | Endogenous tripeptide synthesized in virtually all mammalian cells from L-glutamate, L-cysteine, and glycine via a two-step ATP-dependent enzymatic process (GCL and GS) |
| Classification | Endogenous Tripeptide Antioxidant / Redox Modulator / Research Compound |
| Half-Life | Plasma half-life < 3 minutes (IV administration); intracellular turnover regulated by γ-glutamyl cycle |
| Bioavailability | Low oral bioavailability due to intestinal hydrolysis by γ-glutamyl transpeptidase (GGT); enhanced by liposomal or sublingual delivery |

**Identifiers:**
- Purity Standard: ≥98% by HPLC
- Synonyms: GSH, L-Glutathione, Reduced Glutathione, γ-L-glutamyl-L-cysteinylglycine, Isethion, Tathione, Glutatiol
- InChI Key: RWSXRVCMGQZWBV-WDSKDSINSA-N
- SMILES: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O)C(O)=O
- InChI: InChI=1S/C10H17N3O6S/c11-5(10(18)19)1-2-7(14)13-6(4-20)9(17)12-3-8(15)16/h5-6,20H,1-4,11H2,(H,12,17)(H,13,14)(H,15,16)(H,18,19)/t5-,6-/m0/s1

**Overview:**

### Research Overview

      Glutathione (GSH) is a ubiquitous endogenous tripeptide that serves as the principal intracellular antioxidant and redox buffer in mammalian biology. Composed of L-glutamate, L-cysteine, and glycine, it was first isolated and named by Frederick Gowland Hopkins in 1921, though its correct tripeptide structure was not established until 1935 by Harington and Mead. Present at millimolar concentrations (0.5&ndash;10 mM) in virtually every cell, GSH participates in a vast network of antioxidant defense, detoxification, signal transduction, and immune modulation processes that are essential for cellular survival.[3][12]

      GSH is biosynthesized in the cytosol via a tightly regulated, two-step ATP-dependent enzymatic process. First, glutamate-cysteine ligase (GCL) catalyzes the formation of &gamma;-glutamylcysteine from glutamate and cysteine (the rate-limiting step); then glutathione synthetase (GS) adds glycine to the C-terminal to yield the final molecule. The availability of cysteine is the primary rate-limiting factor in this synthesis. The liver serves as the principal production organ and the main source of plasma GSH for interorgan distribution.[12][20]

      The therapeutic rationale for GSH research is grounded in its role as the body's "master antioxidant." GSH directly neutralizes reactive oxygen species (ROS) and reactive nitrogen species (RNS), serves as the essential cofactor for glutathione peroxidases (GPx), and conjugates with electrophilic toxins and heavy metals via glutathione S-transferases (GSTs) for excretion (Phase II detoxification). The ratio of reduced GSH to oxidized GSSG serves as a fundamental index of cellular oxidative status; a decline in this ratio is a hallmark of oxidative stress, cellular dysfunction, and aging.[3][12]

      Clinical research has established that GSH depletion is implicated in the pathology of numerous conditions. In Parkinson's disease, GSH depletion in the substantia nigra precedes neurodegeneration, and intranasal GSH (600 mg/day) improved UPDRS scores in a Phase IIb trial (P = 0.0025).[11][5] In liver disease, oral GSH (300 mg/day) significantly reduced alanine transaminase (ALT) in NAFLD patients.[8] In dermatology, both oral (250&ndash;500 mg/day) and topical (2% GSSG) glutathione demonstrated significant reductions in melanin index, wrinkles, and improvements in skin elasticity in multiple randomized controlled trials.[19][18][2] In type 2 diabetes, 1000 mg/day oral GSH significantly improved whole-body insulin sensitivity in obese males.[16] As a chemotherapy adjunct, IV glutathione (1.5 g/m&sup2;) reduced cisplatin-associated neurotoxicity in gastric and ovarian cancer patients without compromising antineoplastic efficacy.[4][15]

      A key challenge in GSH research is bioavailability. Standard oral GSH has limited systemic availability due to degradation by intestinal &gamma;-glutamyl transpeptidase (GGT), and IV administration yields a plasma half-life of less than 3 minutes. Strategies to overcome this include liposomal encapsulation, sublingual delivery, intranasal administration (which increases brain GSH >200% within 45 minutes), and the use of GSH precursors such as N-acetylcysteine (NAC).[14][20][9]

**Mechanism of Action:**

### Mechanism of Action

      Glutathione (GSH) does not function through a single classical receptor-ligand interaction. Instead, it acts as a pervasive biochemical modulator of cellular redox state, enzymatic cofactor, and signaling regulator via post-translational protein modification.[3]

      #### Primary Biochemical Targets & Binding Characteristics

      
        Target / MechanismDetailEvidence
        
          S-GlutathionylationReversible post-translational modification; GSH forms mixed disulfide bonds with reactive cysteine residues on target proteins (protein-SSG), acting as a redox "on/off" switch for regulatory, structural, and metabolic proteinsBallatori et al. (2009)[3]
          Glutathione Peroxidases (GPx)GSH serves as the essential electron donor for GPx-catalyzed reduction of H2O2 and lipid hydroperoxides to water/alcohols, oxidizing GSH to GSSGBallatori et al. (2009)[3]
          Glutathione S-Transferases (GSTs)GSH conjugates with electrophilic xenobiotics, heavy metals (Hg, Pb), and endogenous toxins (Phase II detoxification), rendering them water-soluble for excretionBallatori et al. (2009)[3]
          Metal ChelationSix coordination sites for metal ions; thiol group has high affinity for Cu, Zn, Hg, and Pb, forming stable mercaptide complexes for mobilization and transportBallatori et al. (2009)[3]
          NMDA Receptor ModulationGSH modulates the N-methyl-D-aspartate (NMDA) receptor, regulating calcium influx in cerebellar granule cellsBallatori et al. (2009)[3]
          Bcl-2 BindingGSH binds the Bcl-2 BH3-domain groove at the mitochondria, contributing to anti-apoptotic antioxidant functionBallatori et al. (2009)[3]
          &gamma;-Peptide Bond StabilityUnusual &gamma;-carboxyl linkage between glutamate and cysteine protects from intracellular peptidase hydrolysis; only cleaved by ectoenzyme &gamma;-glutamyl transpeptidase (GGT) on external cell surfacesBallatori et al. (2009)[3]
        
      

      #### Downstream Signaling Cascades

      
        PathwayMechanismOutcome
        
          Keap1-Nrf2-AREOxidative stress or electrophiles modify Keap1 cysteines, preventing Nrf2 degradation; stabilized Nrf2 translocates to nucleus and binds Antioxidant Response Element (ARE); modulated by ERK and p38 MAPK kinasesTranscription of GSH synthesis genes (GCLC, GCLM) and detoxification enzymes (GSTs)[3]
          NF-&kappa;B SignalingS-glutathionylation of the p50 subunit of NF-&kappa;B inhibits its DNA binding; GSH depletion activates NF-&kappa;B via ROS-mediated I&kappa;B degradationGSH suppresses pro-inflammatory gene transcription (TNF-&alpha;, IL-1&beta;, IL-6); depletion drives inflammation[3]
          MAPK PathwaySevere GSH depletion oxidizes MAPK phosphatases (MKPs), causing sustained JNK and p38 MAPK activation; GST-pi monomers bind JNK (inhibition), but dimerize under oxidative stress to release JNKCytochrome c release and caspase activation leading to apoptosis[3]
          Nitric Oxide (NO) SignalingGSH buffers NO; depletion increases free NO causing protein nitration and DNA damage; activates p53, which induces PGC-1&alpha; for antioxidant responseModulation of NO-mediated signaling and protection against nitrosative stress[3]
        
      

      #### Cellular & Tissue-Level Effects

      
        SystemEffectDetail
        
          MitochondriaCritical for neutralizing H2O2 from electron transport chainTransported via dicarboxylate and 2-oxoglutarate carriers; prevents mPTP opening[3]
          Skin (Antimelanogenic)Inhibits tyrosinase by chelating copper at active siteShifts melanogenesis from eumelanin (dark) to pheomelanin (light); reduces melanin index, wrinkles, increases elasticity[19]
          Nervous SystemAstrocytes synthesize and release GSH for neuronal uptakeProtects dopaminergic neurons from oxidative damage; preserves mitochondrial Complex I activity[5]
          Immune SystemEssential for T-cell metabolic reprogramming and clonal expansionGSH:GSSG ratio modulates Th1/Th2 balance; depletion favors Th2 (chronic inflammation)[14]
          CardiovascularRestores endothelium-dependent vasorelaxation in agingIncreases H2S levels and mtNOS activity; inhibits mPTP opening in aged heart tissue[3]
          HepatoprotectiveReduces ALT and oxidative damage markers in liver tissueSignificant benefit in NAFLD and NASH models[8]
        
      

      #### Comparison with Related Compounds

      
        CompoundRelationship to GSHKey Difference
        
          L-CysteineRate-limiting precursor substrate for GSH synthesisNeurotoxic at high extracellular concentrations; GSH is the non-toxic storage form[3]
          N-Acetylcysteine (NAC)Deacetylated precursor used to replenish intracellular GSHBetter oral bioavailability than GSH; widely used clinically as GSH booster[7]
          GSSG (Oxidized Glutathione)Disulfide dimer formed when GSH is oxidizedAccumulation is toxic; cells maintain GSH:GSSG ratio >100:1 via Glutathione Reductase + NADPH[3]
          Liposomal GlutathioneGSH encapsulated in phospholipid vesiclesEnhanced oral absorption bypassing GGT degradation; elevates body stores and immune markers[14]
          Glutathione Monoethyl Ester (GEE)Synthetic analog designed for enhanced cell penetrationBypasses transport limitations; crosses blood-brain barrier more effectively than native GSH[3]

**Research Applications:**

### Research Applications

      Glutathione is investigated across a broad spectrum of research domains, with evidence spanning preclinical animal models to randomized controlled clinical trials:

      #### 1. Neurodegenerative Diseases (Parkinson's, Alzheimer's)

      GSH depletion in the substantia nigra is one of the earliest biochemical changes in Parkinson's disease, preceding mitochondrial Complex I dysfunction and dopaminergic neuron loss. Intranasal GSH (200&ndash;600 mg/day) demonstrated significant improvement in UPDRS Total scores (-4.6 points, P = 0.0025) in a Phase IIb RCT, and a single 200 mg intranasal dose increased brain GSH levels >200% within 45 minutes (P < 0.001) as measured by magnetic resonance spectroscopy.[11][5][13]

      #### 2. Hepatoprotection (NAFLD, NASH, Cirrhosis)

      GSH is extensively studied for its hepatoprotective effects. Oral GSH (300 mg/day for 4 months) significantly reduced ALT levels (p < 0.05) in NAFLD patients. In NASH patients, 300 mg/day for 3 months decreased both ALT and 8-OHdG (DNA oxidative damage marker) significantly. However, 500 mg/day GSH for 12 weeks showed no significant effect in liver cirrhosis.[8]

      #### 3. Dermatology & Skin Research

      
        StudyInterventionKey ResultRef
        
          Weschawalit et al. (2017)250 mg oral GSH or GSSG/day, 12 weeksSignificant wrinkle reduction (P = 0.006); increased skin elasticity; melanin index reduction in >40 year group[19]
          Arjinpathana et al. (2012)500 mg oral GSH/day, 4 weeksSignificant melanin index reduction in sun-exposed areas (face/wrists) vs placebo[2]
          Watanabe et al. (2014)2% GSSG lotion, twice daily, 10 weeksSignificant reduction in melanin index (p < 0.05), TEWL (p < 0.05), and wrinkles (p < 0.01)[18]
        
      

      #### 4. Diabetes & Metabolic Syndrome

      Research highlights a correlation between GSH insufficiency and T2DM complications. Oral GSH (1000 mg/day, 3 weeks) significantly increased whole-body insulin sensitivity in obese males with and without T2DM (NCT02948673). In a larger trial (n=360), 500 mg/day for 6 months as adjunct therapy significantly decreased oxidative damage markers and improved HbA1c in patients >55 years.[16]

      #### 5. Oncology & Chemotherapy Support

      IV glutathione (1.5 g/m&sup2;) administered before cisplatin chemotherapy demonstrated neuroprotective effects in randomized trials of advanced gastric cancer and ovarian cancer, reducing neurotoxicity and nephrotoxicity without compromising antineoplastic efficacy.[4][15]

      #### 6. Respiratory Conditions (Cystic Fibrosis, IPF)

      Inhaled/aerosolized glutathione (600 mg BID) is investigated for replenishing GSH in the epithelial lining fluid of the lungs. Oral reduced L-glutathione improved growth in pediatric cystic fibrosis patients. Results on FEV1 improvement have been mixed across studies.[17]

      #### 7. Viral Infections & Immune Function

      GSH depletion is linked to impaired host immune responses and severe outcomes in HIV and COVID-19. Liposomal glutathione supplementation elevated body stores of GSH and markers of immune function (including natural killer cell activity) in healthy adults.[14]

      #### 8. Male Infertility

      Intramuscular GSH (600 mg) was studied in a placebo-controlled, double-blind crossover trial for male infertility, targeting oxidative stress in seminal plasma that damages sperm DNA and motility.[10]

      #### 9. Cardiovascular Aging

      In aged Wistar rats, intraperitoneal GSH (52 mg/kg) increased total heart glutathione by 40% (p = 0.0027), reduced superoxide generation 2.5-fold, and restored endothelium-dependent vasorelaxation, demonstrating significant cardiovascular rejuvenation potential.[3]

**Research Summary:**

### Research Summary

      #### Key Clinical Studies

      
        StudyDesign / PopulationKey FindingsRef
        
          Richie et al. (2015)
Eur J NutrRCT, n=54 healthy adults; 250 mg or 1000 mg oral GSH/day, 6 months1000 mg/day: significant increase in GSH in erythrocytes, plasma, lymphocytes, buccal cells (p < 0.05). 250 mg: no significant difference vs placebo[12]
          Mischley et al. (2017)
J Parkinson's DisPhase IIb RCT, n=45 PD patients; 300 or 600 mg/day intranasal GSH, 12 weeks600 mg/day: UPDRS Total improved -4.6 points (P = 0.0025); Motor sub-score improved -2.2 points (P = 0.0485)[11]
          Honda et al. (2017)
BMC GastroenterolOpen-label pilot, n=34 NAFLD patients; 300 mg oral GSH/day, 4 monthsSignificant reduction in ALT (p < 0.05); non-significant improvements in liver stiffness[8]
          S&oslash;nderg&aring;rd et al. (2021)
Appl Physiol Nutr MetabRCT, n=20 obese males &plusmn; T2DM; 1000 mg oral GSH/day, 3 weeksWhole-body insulin sensitivity significantly increased; skeletal muscle GSH increased ~19%[16]
          Weschawalit et al. (2017)
Clin Cosm Invest DermRCT, n=57 healthy females; 250 mg oral GSH or GSSG/day, 12 weeksSignificant wrinkle reduction (P = 0.006); increased skin elasticity; melanin reduction in >40 yrs subgroup[19]
          Cascinu et al. (1995)
J Clin OncolRCT, advanced gastric cancer; 1.5 g/m&sup2; IV GSH before cisplatinNeuroprotective effect; reduced cisplatin-associated neurotoxicity without compromising chemotherapy efficacy[4]
          Smyth et al. (1997)
Ann OncolRCT, ovarian cancer; IV GSH with cisplatinReduced toxicity; improved quality of life; no reduction in antineoplastic efficacy[15]
          Sinha et al. (2018)
Eur J Clin NutrRCT; liposomal GSH supplementationElevated body stores of GSH; enhanced markers of immune function including natural killer cell activity[14]
        
      

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Strutynska et al. (2023)Aged male Wistar rats; 52 mg/kg i.p., acuteHeart GSH +40% (p=0.0027); superoxide reduced 2.5x; H2O2 reduced 2.3x; restored vasorelaxation; inhibited mPTP opening[3]
          Cai et al. (2003)BALB/c mice; oral GSH; influenza A/X-31Decreased viral titers in both lung and trachea homogenates[3]
          Chinta et al. (2007)In vivo GSH depletion in dopaminergic midbrain neuronsInducible GSH alterations result in nigrostriatal degeneration, confirming causative role of GSH loss in PD pathology[5]
        
      

      #### Dosage Summary

      
        SettingDoseRoute / DurationNotes
        
          In Vitro0.5&ndash;10 mMCell culturePhysiological intracellular concentration range
          Animal (Rat)52 mg/kgIntraperitoneal; acuteLD50 > 5 g/kg (mice, oral)
          Human &mdash; Oral (antioxidant)250&ndash;1000 mg/dayOral capsules; 4 weeks&ndash;6 months1000 mg/day required for 6 months to significantly elevate body stores[12]
          Human &mdash; Oral (skin)250&ndash;500 mg/dayOral; 4&ndash;12 weeksSignificant melanin and wrinkle reduction[19][2]
          Human &mdash; Intranasal200&ndash;600 mg/dayIntranasal atomization; 12 weeksBrain GSH >200% increase within 45 min[11]
          Human &mdash; IV1.5 g/m&sup2;Intravenous; before chemotherapyNeuroprotective adjunct to cisplatin[4]
          Human &mdash; Topical2% GSSG lotionTwice daily; 10 weeksSignificant reduction in melanin index, wrinkles, TEWL[18]
          Human &mdash; Inhaled600 mg BIDNebulizedRespiratory conditions; contraindicated in asthma[17]
        
      

      #### Safety Profile

      
        RouteSafety AssessmentAdverse Events
        
          OralGRAS status; well-tolerated; LD50 > 5 g/kg (mice)Mild: flatulence, loose stools, flushing, weight gain[12]
          TopicalGenerally well-toleratedMild erythema, pruritus; typically self-resolving[19]
          IntranasalPhase IIb safety establishedOne withdrawal (tachycardia/cardiomyopathy, resolved upon cessation)[11]
          IntravenousSignificant safety concerns32% adverse event rate; hepatotoxicity, anaphylaxis, Stevens-Johnson syndrome reported
          InhaledContraindicated in asthmaRisk of bronchospasm
        
      

      &x26A0;&xFE0F; Important Disclaimer

This product is sold strictly for in-vitro research and laboratory use only. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law. For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      About This Research Profile

This research profile was compiled from peer-reviewed sources and publicly available scientific literature. All articles and product information provided on this website are for informational and educational purposes only. The information presented here does not constitute medical advice and should not be relied upon as a substitute for consultation with a qualified healthcare professional.

**Citations (20 references):**

- Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. Journal of Alternative and Complementary Medicine, 17(9), 827-833, 2011. — https://pubmed.ncbi.nlm.nih.gov/21875351/
- Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. Journal of Dermatological Treatment, 23(2), 97-102, 2012. — https://pubmed.ncbi.nlm.nih.gov/20524875/
- Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 390(3), 191-214, 2009. — https://pubmed.ncbi.nlm.nih.gov/19166318/
- Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology, 13(1), 26-32, 1995. — https://pubmed.ncbi.nlm.nih.gov/7799033/
- Chinta SJ, Kumar MJ, Hsu M, et al. Inducible alterations of glutathione levels in adult dopaminergic midbrain neurons result in nigrostriatal degeneration. Journal of Neuroscience, 27(51), 13997-14006, 2007. — https://pubmed.ncbi.nlm.nih.gov/18094238/
- Handog EB, Datuin MS, Singzon IA. An open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in Filipino women. International Journal of Dermatology, 55(2), 153-157, 2016. — https://pubmed.ncbi.nlm.nih.gov/26138674/
- Holmay MJ, Terpstra M, Coles LD, et al. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clinical Neuropharmacology, 36(4), 103-106, 2013. — https://pubmed.ncbi.nlm.nih.gov/23860343/
- Honda Y, Kessoku T, Sumida Y, et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterology, 17(1), 96, 2017. — https://pubmed.ncbi.nlm.nih.gov/28789631/
- Kovacs-Nolan J, Rupa P, Matsui T, et al. In vitro and ex vivo uptake of glutathione (GSH) across the intestinal epithelium and fate of oral GSH after in vivo supplementation. Journal of Agricultural and Food Chemistry, 62(39), 9499-9506, 2014. — https://pubmed.ncbi.nlm.nih.gov/25198144/
- Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Human Reproduction, 8(10), 1657-62, 1993. — https://pubmed.ncbi.nlm.nih.gov/8300831/
- Mischley LK, Leverenz JB, Lau RC, et al. A randomized, double-blind phase I/IIa study of intranasal glutathione in Parkinson's disease. Movement Disorders, 30(12), 1696-1701, 2015. — https://pubmed.ncbi.nlm.nih.gov/26224169/
- Richie JP, Nichenametla S, Neidig W, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. European Journal of Nutrition, 54(2), 251-263, 2015. — https://pubmed.ncbi.nlm.nih.gov/24791752/
- Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 20(7), 1159-1170, 1996. — https://pubmed.ncbi.nlm.nih.gov/8938817/
- Sinha R, Sinha I, Calcagnotto A, et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European Journal of Clinical Nutrition, 72(1), 105-111, 2018. — https://pubmed.ncbi.nlm.nih.gov/28853742/
- Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Annals of Oncology, 8(6), 569-73, 1997. — https://pubmed.ncbi.nlm.nih.gov/9266533/
- Søndergård SD, Cintin I, Kuhlman AB, et al. The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Applied Physiology, Nutrition, and Metabolism, 46(9), 1133-1142, 2021. — https://pubmed.ncbi.nlm.nih.gov/33606622/
- Visca A, Bishop CT, Hilton S, Hudson VM. Oral reduced L-glutathione improves growth in pediatric cystic fibrosis patients. Journal of Pediatric Gastroenterology and Nutrition, 60(6), 802-810, 2015. — https://pubmed.ncbi.nlm.nih.gov/25688647/
- Watanabe F, Hashizume E, Chan GP, Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clinical, Cosmetic and Investigational Dermatology, 7, 267-274, 2014. — https://pubmed.ncbi.nlm.nih.gov/25378941/
- Weschawalit S, Thongthip S, Phutrakool P, Asawanonda P. Glutathione and its antiaging and antimelanogenic effects. Clinical, Cosmetic and Investigational Dermatology, 10, 147-153, 2017. — https://pubmed.ncbi.nlm.nih.gov/28490897/
- Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. European Journal of Clinical Pharmacology, 43(6), 667-669, 1992. — https://pubmed.ncbi.nlm.nih.gov/1362956/

**Storage & Handling:**

Lyophilized: -20°C or 2–8°C (stable long-term as dry powder); Reconstituted: aliquot immediately, store at 2–8°C short-term or -20°C long-term; protect from light, air, and moisture; avoid freeze-thaw cycles.

**Author:** Helmut Sies, MD
Helmut Sies, MD, is a pioneering biochemist who formulated the concept of "oxidative stress" and is recognized as a "Redox Pioneer" by the journal Free Radical Biology and Medicine. He received his MD from the University of Munich (1967) and his Habilitation in Physiological Chemistry and Physical B

---

### Ipamorelin

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₃₈H₄₉N₉O₅ |
| Molecular Weight | 711.85 Da |
| CAS Number | 170851-70-4 |
| PubChem CID | 9831659 |
| Sequence (1-letter) | XHXFK (X = non-proteinogenic amino acids) |
| Sequence (3-letter) | Aib-His-D-2-Nal-D-Phe-Lys-NH₂ |
| Structure | Linear pentapeptide; contains Aib (α-methylalanine) and D-2-naphthylalanine; C-terminal amide |
| InChI Key | NEHWBYHLYZGBNO-BVEPWEIPSA-N |
| Origin | Synthetic — derived from GHRP-1 (Novo Nordisk) |
| Classification | Growth Hormone Secretagogue / Ghrelin Mimetic / Research Peptide |
| Plasma Half-Life | ~2 hours (human); ~30–60 min (rat) |

**Identifiers:**
- Purity Standard: ≥95–98% by RP-HPLC
- IUPAC Name: (2S)-6-Amino-2-[[(2R)-2-[[(2R)-2-[[(2S)-2-[(2-amino-2-methylpropanoyl)amino]-3-(4H-imidazol-4-yl)propanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]-3-phenylpropanoyl]amino]hexanamide
- SMILES: CC(C)(C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@H](CC2=CC3=CC=CC=C3C=C2)C(=O)N[C@H](CC4=CC=CC=C4)C(=O)N[C@@H](CCCCN)C(=O)N)N
- UNII Code: Y9M3S784Z6
- Monoisotopic Mass: 711.385 Da
- Solubility: Free base: 0.0032 mg/mL (water); Acetate salt: 5 mg/mL (water)

**Overview:**

### Research Overview

      Ipamorelin (NNC 26-0161) is a synthetic pentapeptide growth hormone secretagogue with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH₂, developed by Novo Nordisk in the mid-1990s by systematic modification of GHRP-1. It acts as a highly selective agonist of the GHS-R1a receptor (ghrelin receptor), stimulating potent, pulsatile growth hormone release without affecting ACTH, cortisol, FSH, LH, TSH, or prolactin — even at 200× the effective dose.[1][2]

      Ipamorelin research spans 8+ indication categories including selective GH secretion, postoperative ileus, bone growth, body composition, insulin secretion, pain modulation, and cancer cachexia. A Phase II clinical trial for POI (n=114, NCT00672074) failed to reach statistical significance, and clinical development was discontinued.[6][4]

      Key distinguishing features include: (1) first selective GHS with GHRH-like specificity, (2) no somatotroph desensitization upon chronic administration, (3) linear pharmacokinetics in humans (T½ ~2h), and (4) GH-independent adipogenic effects.[1][9]

**Mechanism of Action:**

### Mechanism of Action

      Ipamorelin activates the GHS-R1a (ghrelin receptor) on pituitary somatotroph cells with an in vitro EC₅₀ of 1.3 ± 0.4 nmol/L and in vivo ED₅₀ of 2.3 nmol/kg (swine). Binding triggers phospholipase C (PLC) activation via Gα₁₁/q → IP3 → intracellular Ca²⁺ release → GH vesicle exocytosis — a pathway distinct from GHRH's cAMP signaling.[1][2]

      #### Receptor & Signaling Profile

      
        TargetActionDownstream Effect
        
          GHS-R1a (Ghrelin Receptor)Selective agonistPLC → IP3 → Ca²⁺ → GH vesicle exocytosis
          cAMP (Synergistic)Enhances pre-stimulated adenylyl cyclaseSynergistic GH release when combined with GHRH
          Enteric Cholinergic NeuronsActivates excitatory neurons (atropine/TTX-sensitive)Accelerates gastric motility and emptying
        
      
      Ipamorelin's selectivity is exceptional: it does NOT stimulate ACTH, cortisol, FSH, LH, prolactin, or TSH — even at doses 200× the ED₅₀. Additionally, chronic administration does not desensitize somatotrophs, unlike GHRH which induces homologous down-regulation.[1][7]

      In humans, Ipamorelin exhibits linear pharmacokinetics with a T½ of ~2 hours, SC₅₀ of 214 nmol/L, and triggers a single episodic GH burst peaking at 0.67 hours post-administration.[2]

      #### vs. Related Compounds

      
        FeatureIpamorelinGHRP-6 / GHRP-2GHRH
        
          SelectivityHIGH — GH onlyLOW — GH + ACTH + cortisol + prolactinSelective for GH
          DesensitizationNOPartialYES (homologous)
          Primary SignalingPLC / Ca²⁺PLC / Ca²⁺cAMP
          Half-Life (Human)~2 hoursShorter (5× faster clearance)Minutes

**Research Applications:**

### Research Applications

      Ipamorelin research spans 8+ indication categories across GH physiology, GI motility, musculoskeletal biology, and pain:

      
        - Selective GH Secretion — Pulsatile GH release without ACTH/cortisol effects; potency comparable to GHRP-6 but with GHRH-like selectivity.[1]

        - Postoperative Ileus (POI) — Accelerates gastric emptying via GHS-R1a on cholinergic neurons; reduces stomach retention to <25% (vs 78% vehicle). Phase II trial failed (p=0.15).[4][6]

        - Bone Growth & Metabolism — Dose-dependent longitudinal bone growth (42→52 µm/day, p<0.0001); increased tibial/vertebral BMC in adult rats.[3][8]

        - Glucocorticoid-Induced Catabolism — Counteracts GC-induced decreases: periosteal bone formation rate increased 4-fold; increased maximum tetanic muscle tension.[12]

        - Body Composition & Adiposity — GH-independent adipogenic effects; increases food intake and serum leptin in both GH-deficient and GH-intact mice.[9]

        - Insulin Secretion — Stimulates insulin release via calcium channels and adrenergic receptor pathways in normal and diabetic pancreatic tissue.[10]

        - Pain Modulation / Nociception — Attenuates visceral and somatic nociception via peripheral ghrelin receptors; dose-dependent reduction in visceromotor response.[17]

        - Cancer Cachexia / Emesis — Inhibits cisplatin-induced weight loss in ferrets; confirmed efficacy in non-rodent wasting model.[14]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Raun et al. (1998)Rats/Swine — IV bolusED₅₀ = 80 nmol/kg (rats), 2.3 nmol/kg (swine); NO ACTH/cortisol even at >200× ED₅₀; first selective GHS[1]
          Johansen et al. (1999)Adult female rats — 18–450 µg/day SC × 15dLongitudinal bone growth 42→52 µm/day (p<0.0001); dose-dependent[3]
          Andersen et al. (2001)Rats — GC-induced catabolism — 100 µg/kg SC TID × 3moPeriosteal bone formation rate increased 4-fold; increased maximum tetanic muscle tension[12]
          Venkova et al. (2009)Rats with POI — 0.014–1.0 mg/kg IVGastric retention reduced to <25% (vs 78% vehicle, p<0.05); accelerated colonic transit[4]
          Svensson et al. (2000)Female rats — 0.5 mg/kg/day SC × 12 wkIncreased tibial and vertebral BMC; bone dimensions increased (not density)[8]
          Jiménez-Reina et al. (2002)Female Wistar rats — 100 µg/kg SC × 21d67% increase in basal GH release; NO somatotroph desensitization; significant weight gain[7]
          Lall et al. (2001)GH-deficient (lit/lit) mice — 250 µg/kg SC BID × 2–9 wkBody weight +15–17%; increased adiposity via GH-independent mechanism[9]
          Adeghate & Ponery (2004)Normal/diabetic rat tissue — 10⁻¹² to 10⁻⁶ M in vitroSignificant insulin release (p<0.04); via calcium channels and adrenergic pathways[10]
          Mohammadi et al. (2020)Rat visceral hypersensitivity — 0.01–1.0 mg/kg IVDose-dependent reduction in visceromotor response; blocked by ghrelin receptor antagonist[17]
          Lu et al. (2024)Ferrets — cisplatin-induced wastingInhibited cisplatin-induced weight loss; confirmed non-rodent cachexia model[14]
        
      

      #### Clinical Trials

      
        TrialPopulationInterventionKey ResultsRef
        
          Phase I PK/PDn=48 healthy males5 dose levels (4.21–140.45 nmol/kg IV × 15 min)Linear kinetics; T½ ~2h; SC₅₀ = 214 nmol/L; episodic GH burst peaking at 0.67h; no adverse events[2]
          Phase II POI (NCT00672074)n=114 bowel resection patients0.03 mg/kg IV BID × 7 daysMedian meal tolerance: 25.3h vs 32.6h placebo — NOT significant (p=0.15); hypokalemia 12.5%, hyperglycemia 14.3%; 2 fatal SAEs in treatment group; TRIAL FAILED[6]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          SelectivityNo ACTH, cortisol, FSH, LH, PRL, or TSH stimulation — even at 200× ED₅₀
          Phase I (n=48)No adverse events in healthy volunteers
          Phase II (n=114)Hypokalemia 12.5% vs 3.4% placebo; insomnia 10.7% vs 5.2%; hyperglycemia 14.3% vs 8.6%; 2 fatal SAEs
          ReproductiveClass-wide concern: ghrelin receptor agonists may negatively impact fertilization/embryofetal development (mouse models)
          Drug InteractionsReverses morphine-induced GI slowing; blocked by GHS receptor antagonists; not affected by GHRH antagonists
          PharmacokineticsIntranasal ~20% bioavailability; oral 
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (21 references):**

- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561. — https://doi.org/10.1530/eje.0.1390552
- Gobburu JVS, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412-1416. — https://pubmed.ncbi.nlm.nih.gov/10496658/
- Johansen PB, Nowak J, Skjaerbaek C, et al. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Hormone & IGF Research. 1999;9(2):106-113. — https://doi.org/10.1054/ghir.1999.9998
- Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. JPET. 2009;329(3):1110-1116. — https://doi.org/10.1124/jpet.108.149211
- Greenwood-Van Meerveld B, Tyler K, Mohammadi E, Pietra C. Efficacy of ipamorelin on gastric dysmotility in a rodent model of postoperative ileus. Journal of Experimental Pharmacology. 2012;4:149-155. — https://doi.org/10.2147/JEP.S35396
- Beck DE, Sweeney WB, McCarter MD. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-1534. — https://doi.org/10.1007/s00384-014-2030-8
- Jiménez-Reina L, Cañete R, de la Torre MJ, Bernal G. Chronic in vivo Ipamorelin treatment stimulates body weight gain and growth hormone release in vitro in young female rats. European Journal of Anatomy. 2002;6(1):37-45. — https://pubmed.ncbi.nlm.nih.gov/
- Svensson J, Lall S, Dickson SL, Jansson JO. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. Journal of Endocrinology. 2000;165:569-577. — https://pubmed.ncbi.nlm.nih.gov/
- Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. BBRC. 2001;280(1):132-138. — https://doi.org/10.1006/bbrc.2000.4065
- Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuro Endocrinology Letters. 2004;25(6):403-406. — https://pubmed.ncbi.nlm.nih.gov/15665799/
- Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin with emphasis on nasal absorption. Xenobiotica. 1998;28(11):1083-1092. — https://doi.org/10.1080/004982598238976
- Andersen NB, Malmlöf K, Johansen PB, Oxlund H. The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats. Growth Hormone & IGF Research. 2001;11(5):266-272. — https://pubmed.ncbi.nlm.nih.gov/
- Hansen TK, Ankersen M, Raun K, Hansen BS. Highly Potent Growth Hormone Secretagogues: Hybrids of NN703 and Ipamorelin. Bioorganic & Medicinal Chemistry Letters. 2001;11(14):1915-1918. — https://pubmed.ncbi.nlm.nih.gov/
- Lu Z, Ngan MP, Liu JYH, Rudd JA. The GHS-R1a agonists anamorelin and ipamorelin inhibit cisplatin-induced weight loss in ferrets. Physiology & Behavior. 2024. — https://pubmed.ncbi.nlm.nih.gov/
- Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational Andrology and Urology. 2020;9(Suppl 2):S149-S159. — https://doi.org/10.21037/tau.2019.11.30
- Thøgersen H, Johansen NL, Lau J, et al. A New Series of Highly Potent Growth Hormone-Releasing Peptides Derived from Ipamorelin. Journal of Medicinal Chemistry. 1998;41. — https://pubmed.ncbi.nlm.nih.gov/
- Mohammadi E, Bhatt V, Bhatt AB, Pietra C, Greenwood-Van Meerveld B. Ipamorelin attenuates visceral and somatic nociception through peripheral ghrelin receptor mechanisms. 2020. — https://pubmed.ncbi.nlm.nih.gov/
- U.S. Food & Drug Administration. FDA Evaluation of Ipamorelin-Related Bulk Drug Substances. FDA Pharmacy Compounding Advisory Committee. 2024. — https://www.fda.gov/
- World Anti-Doping Agency. WADA Prohibited List — S2: Peptide Hormones, Growth Factors, Related Substances, and Mimetics. 2024. — https://www.wada-ama.org/
- Polvino WJ. Methods of treatment using a ghrelin receptor agonist. US Patent 8,039,456 B2. — https://patents.google.com/
- Thøger Nielsen K, et al. Validated screening method for GH-releasing peptides using UHPLC-HRMS on dried blood spots. Drug Testing and Analysis. 2021. — https://pubmed.ncbi.nlm.nih.gov/

**Storage & Handling:**

Lyophilized: -18°C to -20°C (stable several years); Reconstituted: 4°C (2-3 weeks); protect from light.

**Author:** Kirsten Raun
Kirsten Raun is a researcher at Novo Nordisk (Health Care Discovery, Department of GH Biology). Raun was the lead researcher in the original characterization of Ipamorelin, identifying it as the first growth hormone secretagogue with high selectivity for GH release without significantly stimulating 

---

### Kisspeptin

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Gene | KISS1 (chromosome 1q32, human) |
| Precursor Size | 145 amino acids (prepro-kisspeptin) |
| Molecular Weight (Kp-54) | ~5.9 kDa |
| Molecular Weight (Kp-10) | ~1.3 kDa |
| Sequence (Kp-10, Human) | YNWNSFGLRF-NH₂ (Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH₂) |
| Sequence (Kp-10, Rodent) | YNWNSFGLRY-NH₂ |
| C-Terminal Motif | RF-amide (Arg-Phe-NH₂) — critical for KISS1R binding |
| Receptor | KISS1R (GPR54/AXOR12) — Class A rhodopsin-like GPCR |
| Isoforms | Kp-54, Kp-14, Kp-13, Kp-10 (all share C-terminal decapeptide) |
| Synonyms | Metastin, KiSS-1-derived peptide, Kp-54, Kp-14, Kp-13, Kp-10 |
| Analogs | MVT-602 (TAK-448), TAK-683 |
| Plasma Half-Life | Kp-10 ~4 min; Kp-54 ~27.6 min (IV); MVT-602 peaks at 21h |

**Identifiers:**
- Purity Standard: ≥97% by RP-HPLC
- Identity Confirmation: ESI-MS + Amino Acid Analysis
- Endotoxin: Negative by LAL assay
- Sterility: Confirmed by sterility culture

**Overview:**

### Overview

      Kisspeptin refers to a family of neuropeptides derived from the KISS1 gene, originally discovered in 1996 by Danny R. Welch and J.H. Lee in Hershey, Pennsylvania, as a melanoma metastasis suppressor. The gene was named "KiSS-1" to honor the discovery location near the Hershey's Kisses chocolate factory, with "SS" denoting "suppressor sequence."[1]

      The KISS1 gene encodes a 145-amino acid prepro-kisspeptin precursor that undergoes proteolytic cleavage to produce four biologically active isoforms: Kisspeptin-54 (Kp-54), Kp-14, Kp-13, and Kp-10. All isoforms share a conserved C-terminal decapeptide containing an RF-amide motif (Arg-Phe-NH₂) essential for binding and activating the KISS1R (GPR54) receptor.[2][3]

      Kp-54 is the major circulating form with a half-life of ~27.6 minutes; the shorter Kp-10 (~4 min half-life) exhibits full intrinsic bioactivity and is highly conserved across species.[5]

      In 2003, Stephanie Seminara and colleagues made the landmark discovery that loss-of-function mutations in KISS1R (GPR54) cause idiopathic hypogonadotropic hypogonadism and pubertal failure — establishing kisspeptin as the gatekeeper of sexual maturation.[4]

      Kisspeptin is currently investigational — not approved by the FDA or EMA for general clinical use. It is prohibited by WADA under S2 (Peptide Hormones, Growth Factors) as it stimulates LH/FSH/testosterone production.[7]

**Mechanism of Action:**

### Mechanism of Action

      #### KISS1R (GPR54) Receptor Binding

      Kisspeptin acts by binding KISS1R (GPR54/AXOR12), a rhodopsin-like Class A GPCR sharing ~45% identity with galanin receptors (but does not bind galanin). The essential pharmacophore is the C-terminal RF-amide motif; key residues Phe-6 and Arg-9 (Kp-10 numbering) are critical for binding. Cryo-EM studies reveal an orthosteric pocket spanning TM2–7 plus ECL1–3.[2][3]

      #### Primary Gαq/11–PLC–Ca²⁺ Pathway

      KISS1R couples primarily to Gαq/11, activating phospholipase C beta (PLCβ), which hydrolyzes PIP₂ into IP₃ and DAG. IP₃ triggers biphasic intracellular Ca²⁺ release from the endoplasmic reticulum; DAG + Ca²⁺ activates PKC.[8]

      #### MAPK and Additional Cascades

      Downstream signaling involves robust, sustained ERK1/2 phosphorylation (via PKC-dependent and β-arrestin pathways), p38 MAPK activation, arachidonic acid release, and PI3K/Akt signaling.[8]

      #### GnRH Neuronal Excitation

      In GnRH neurons, kisspeptin activates TRPC channels (cation influx) and simultaneously closes Kir channels (preventing K⁺ efflux), causing sustained depolarization and increased action potential firing → pulsatile GnRH secretion → LH/FSH release.[8]

      #### Desensitization (β-Arrestin–Mediated)

      Continuous kisspeptin exposure recruits β-arrestin 1/2, causing receptor internalization via clathrin-coated pits → paradoxical HPG axis suppression. This is exploited therapeutically: TAK-448 continuous exposure suppresses testosterone to castrate levels for prostate cancer research.[9][14]

      #### Isoform Pharmacokinetic Comparison

      
        IsoformHalf-LifeRouteNotes
        
          Kp-54~27.6 minIVMajor circulating form; SC extends to ~1.7h
          Kp-10~4 minIVFull intrinsic bioactivity; highly conserved
          MVT-602 (TAK-448)Peak at ~21hSCMMP-resistant; >4x AUC vs Kp-54

**Research Applications:**

### Research Applications

      Kisspeptin is one of the most extensively studied reproductive neuropeptides, with >1,000 human subjects across Phase 1/2 clinical trials:

      
        - IVF Oocyte Maturation Trigger — SC Kp-54 (3.2–12.8 nmol/kg) triggers oocyte maturation with 95% mature oocytes, 45.1% live birth rate, and no clinically significant OHSS (vs high OHSS risk with hCG).[10][11]

        - Hypothalamic Amenorrhea — Restores LH pulsatility; twice-weekly dosing sustains LH ~9 IU/L over 8 weeks without complete desensitization. Intranasal delivery validated in HA women.[12][13][19]

        - PCOS — IV KP-10 infusion (4 µg/kg/h × 7h) increases LH from 5.2 to 7.8 IU/L and estradiol levels in women with polycystic ovary syndrome.[15]

        - Psychosexual Disorders (HSDD) — Enhances limbic brain processing (amygdala, hippocampus) for sexual/bonding stimuli; increases penile tumescence up to 55% in men; modulates sexual desire regions in women.[16][17]

        - Metabolic / Fatty Liver Disease — TAK-448 reduces hepatic triglycerides, serum FFA, and ALT in MASLD models via AMPK→SREBP-1c→CIDEA downregulation.[18]

        - Cancer Metastasis Suppression — Originally identified as melanoma/breast cancer metastasis suppressor ("metastin"); inhibits MMP-9 via NF-κB pathway suppression.[1]

        - Prostate Cancer (Androgen Deprivation) — Continuous TAK-448/MVT-602 exposure → receptor desensitization → testosterone suppression to castrate levels (Phase 1 data).[14]

        - Pregnancy Biomarker — Kisspeptin rises 7,000-fold during healthy pregnancy; low levels predict miscarriage/preeclampsia by assessing trophoblast invasion.[20]

        - Bone Health — Promotes osteoblast differentiation, inhibits osteoclast activity; acute Kp-54 increases osteocalcin ~24% in men.[21]

        - Puberty Disorders — Activating/inactivating KISS1/KISS1R mutations linked to precocious/delayed puberty; kisspeptin challenge tests used diagnostically.[4]

        - Intranasal Delivery — First human trial: 12.8 nmol/kg intranasal Kp-54 → rapid LH increase (4.4 IU/L in men); no AEs — validating non-invasive delivery.[19]

        - Metabolic Insulin Signaling — IV Kp-54 increases glucose-stimulated insulin secretion ~35% in healthy men.[22]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Mills et al. (2025)C57BL/6J mice — intranasal Kp-5412.8–50 nM intranasal: dose-dependent LH to 3.6 ng/mL at 25 min (p [19]
          Izarraras et al. (2025)DIAMOND mice — TAK-448 MASLD0.3 nmol/h × 6 weeks: reduced liver triglycerides, serum FFA, ALT (p [18]
          Seminara/Ramaswamy (2006/07)Juvenile rhesus monkeys — IV KP-10200–400 µg/h × 98h: maximal LH at 3h, desensitization by 12h; GnRH bolus still effective but KP-10 bolus was not[23]
          Terse et al. (2021)Dogs — KP-10 1000 µg/kg IV × 14dNOAEL at 1000 µg/kg; peak LH at 5 min post-dose; no toxicity signs[24]
          Thompson et al. (2006)Adult male rats — chronic SC KP-54Chronic SC → testicular degeneration; HPG axis suppression via receptor desensitization[25]
          Dinh et al. (2023)Wistar rats — KP-13 CKD model13–26 µg/day IP × 10d: increased BP, exacerbated CKD markers and uremic cardiomyopathy[26]
        
      

      #### Human Clinical Data (>1,000 Participants)

      
        TrialPopulationDose/RouteKey ResultsRef
        
          Dhillo et al. (2005)n=6 healthy menIV Kp-54 4 pmol/kg/min × 90 min2.6-fold LH increase; first-in-human; no AEs[5]
          Dhillo et al. (2007)n=8 healthy womenSC 0.4 nmol/kgPreovulatory LH rise 20.64 IU/L vs follicular 0.12 IU/L[6]
          Abbara et al. (2015)n=60 IVF, high OHSS riskSC Kp-54 3.2–12.8 nmol/kg95% mature oocytes, 52.9% pregnancy rate, 45.1% live birth rate, no clinically significant OHSS[10]
          Abbara et al. (2017)n=62 IVF RCTSC 9.6 nmol/kg × 2 doses30% live birth rate; 1 case mild OHSS only[11]
          Jayasena et al. (2009)n=10 women with HASC 6.4 nmol/kg 2x daily × 2 wkAcute LH ~24 IU/L; tachyphylaxis to 1.5 IU/L[12]
          Jayasena et al. (2010)n=20 women with HASC 6.4 nmol/kg 2x/week × 8 wkSustained LH ~9 IU/L without complete desensitization[13]
          Mills et al. (2023)n=32 men with HSDDIV Kp-54Penile tumescence ↑55%; enhanced sexual brain processing[17]
          Abbara et al. (2020)n=21 (HV, HA, PCOS)SC MVT-602 0.01–0.03 nmol/kgPeak LH at 21h (vs 4.7h Kp-54); >4x AUC; prolonged action[9]
          Mills et al. (2025)n=34 (men, women, HA)Intranasal Kp-54 12.8 nmol/kgRapid LH ↑4.4 IU/L men; no AEs; non-invasive delivery validated[19]
          Izzi-Engbeaya et al. (2018)n=15 healthy menIV Kp-54Glucose-stimulated insulin secretion ↑35%[22]
          Comninos et al. (2022)n=26 healthy menAcute Kp-54Osteocalcin ↑24% (bone formation marker)[21]
        
      

      #### Safety Summary: >1,000 Human Exposures

      
        ParameterFinding
        
          Common AEsMild/transient: injection site reactions, headache, nausea, bloating
          CardiotoxicityNone — no changes in HR, BP, or ECG
          TachyphylaxisContinuous high-dose → β-arrestin recruitment → receptor internalization → HPG suppression (physiological, not toxic)
          Dog NOAEL1000 µg/kg IV × 14 days — no toxicity
          MetabolismCleaved by MMP-2, MMP-9, furin; C-terminal cleavage inactivates
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (30 references):**

- Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. Journal of the National Cancer Institute. 1996;88(23):1731-1737. — https://doi.org/10.1093/jnci/88.23.1731
- Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613-617. — https://doi.org/10.1038/35079135
- Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. Journal of Biological Chemistry. 2001;276(37):34631-34636. — https://doi.org/10.1074/jbc.M104847200
- Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. New England Journal of Medicine. 2003;349(17):1614-1627. — https://doi.org/10.1056/NEJMoa035322
- Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. Journal of Clinical Endocrinology & Metabolism. 2005;90(12):6609-6615. — https://doi.org/10.1210/jc.2005-1468
- Dhillo WS, Chaudhri OB, Thompson EL, et al. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. Journal of Clinical Endocrinology & Metabolism. 2007;92(10):3958-3966. — https://doi.org/10.1210/jc.2007-1116
- World Anti-Doping Agency. The Prohibited List. S2 Peptide Hormones, Growth Factors, Related Substances, and Mimetics. WADA. Updated 2025. — https://www.wada-ama.org/en/prohibited-list
- de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proceedings of the National Academy of Sciences. 2003;100(19):10972-10976. — https://doi.org/10.1073/pnas.1834399100
- Abbara A, Eng PC, Phylactou M, et al. Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. Journal of Clinical Investigation. 2020;130(12):6739-6753. — https://doi.org/10.1172/JCI139681
- Abbara A, Jayasena CN, Christopoulos G, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of OHSS during IVF therapy. Journal of Clinical Endocrinology & Metabolism. 2015;100(9):3322-3331. — https://doi.org/10.1210/jc.2015-2332
- Abbara A, Clarke S, Islam R, et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of OHSS: a phase 2 randomized controlled trial. Human Reproduction. 2017;32(9):1915-1924. — https://doi.org/10.1093/humrep/dex253
- Jayasena CN, Nijher GM, Chaudhri OB, et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. Journal of Clinical Endocrinology & Metabolism. 2009;94(11):4315-4323. — https://doi.org/10.1210/jc.2009-0406
- Jayasena CN, Nijher GM, Abbara A, et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clinical Pharmacology & Therapeutics. 2010;88(6):840-847. — https://doi.org/10.1038/clpt.2010.204
- MacLean DB, Matsui H, Suri A, Neuwirth R, Colombel M. Sustained exposure to the investigational kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer. Journal of Clinical Endocrinology & Metabolism. 2014;99(8):E1445-E1453. — https://doi.org/10.1210/jc.2013-4236
- Skorupskaite K, et al. KP-10 infusion in PCOS women. Human Reproduction. 2020. — https://doi.org/10.1093/humrep/
- Comninos AN, Wall MB, Demetriou L, et al. Kisspeptin modulates sexual and emotional brain processing in humans. Journal of Clinical Investigation. 2017;127(2):709-719. — https://doi.org/10.1172/JCI89519
- Mills EG, et al. HSDD in men — kisspeptin increases penile tumescence and sexual brain processing. JAMA Network Open. 2023. — https://pubmed.ncbi.nlm.nih.gov/
- Izarraras L, et al. Kisspeptin agonist reduces hepatic de novo lipogenesis in MASLD via AMPK-SREBP-1c-CIDEA. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Mills EG, et al. Intranasal kisspeptin-54 rapidly stimulates gonadotropin release in humans: a non-invasive delivery route. eBioMedicine. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Jayasena CN, Abbara A, et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. Journal of Clinical Investigation. 2014;124(8):3667-3677. — https://doi.org/10.1172/JCI75730
- Comninos AN, et al. Acute kisspeptin administration increases osteocalcin in healthy men. Journal of Clinical Endocrinology & Metabolism. 2022. — https://pubmed.ncbi.nlm.nih.gov/
- Izzi-Engbeaya C, et al. Kisspeptin increases glucose-stimulated insulin secretion in healthy men. Diabetes, Obesity and Metabolism. 2018. — https://pubmed.ncbi.nlm.nih.gov/
- Seminara SB, et al. Continuous human metastin 45-54 infusion desensitizes GPR54-induced GnRH release in juvenile male rhesus monkeys. 2006. — https://pubmed.ncbi.nlm.nih.gov/
- Terse PS, et al. Kisspeptin-10 toxicology studies in dogs — NOAEL at 1000 µg/kg IV × 14 days. 2021. — https://pubmed.ncbi.nlm.nih.gov/
- Thompson EL, et al. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. 2006. — https://pubmed.ncbi.nlm.nih.gov/
- Dinh TO, et al. Kisspeptin-13 exacerbates chronic kidney disease and uremic cardiomyopathy in rats. 2023. — https://pubmed.ncbi.nlm.nih.gov/
- George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. Journal of Clinical Endocrinology & Metabolism. 2011;96(8):E1228-E1236. — https://doi.org/10.1210/jc.2011-0089
- Thurston L, et al. Kisspeptin modulates brain activity in sexual desire regions in women with HSDD. JAMA Network Open. 2022. — https://pubmed.ncbi.nlm.nih.gov/
- Nishizawa N, Takatsu Y, et al. Design and synthesis of TAK-448, an investigational nonapeptide KISS1R agonist. Journal of Medicinal Chemistry. 2016;59(19):8804-8811. — https://doi.org/10.1021/acs.jmedchem.6b00379
- Chan YM, Butler JP, Pinnell NE, et al. Kisspeptin resets the hypothalamic GnRH clock in men. Journal of Clinical Endocrinology & Metabolism. 2011;96(6):E908-E915. — https://doi.org/10.1210/jc.2010-3046

**Storage & Handling:**

Store lyophilized kisspeptin at −20°C. Reconstituted Kp-54 in 0.9% saline stable for 60 days at 4°C (>90% retention). Intranasal solution: 3.5 mg/mL in 0.9% saline. Avoid repeated freeze-thaw.

**Author:** Prof. Waljit S. Dhillo
Waljit S. Dhillo, BSc MBBS PhD, is Professor of Endocrinology and Metabolism at Imperial College London, Department of Investigative Medicine. Prof. Dhillo conducted the first-in-human kisspeptin administration studies in men (2005) and women (2007), establishing kisspeptin as a potent stimulator of

---

### Kpv

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₆H₃₀N₄O₄ |
| Molecular Weight | 342.44 g/mol (378.47 for Ac-KPV-NH₂) |
| CAS Number | 107715-88-8 |
| Sequence (3-letter) | Lys-Pro-Val |
| Sequence (1-letter) | KPV |
| Amino Acids | 3 (linear tripeptide) |
| Structural Type | Linear tripeptide; often synthesized with N-acetylation and C-terminal amidation (Ac-KPV-NH₂) |
| Parent Molecule | α-MSH (alpha-melanocyte-stimulating hormone), amino acids 11–13 |
| Synonyms | α-MSH(11-13), alpha-melanocyte-stimulating hormone (11-13), KPV peptide |
| Plasma Half-life | <30 minutes |

**Identifiers:**
- InChI Key: YSPZCHGIWAQVKQ-AVGNSLFASA-N
- Isomeric SMILES: CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCN
- Purity Standard: ≥98% by RP-HPLC
- Endotoxin: ≤10 EU/mg (LAL assay)
- Water Content: ≤6.0% (Karl Fischer)

**Overview:**

### Overview

      KPV (Lys-Pro-Val) is a naturally occurring tripeptide derived from the C-terminal fragment (amino acids 11–13) of alpha-melanocyte-stimulating hormone (α-MSH), a 13-amino acid POMC-derived neuropeptide.[1][2]

      Originally characterized by James M. Lipton and Melanie E. Hiltz in 1989, KPV was identified as the specific molecular fragment responsible for the parent hormone's anti-inflammatory and antipyretic activities — the "active message sequence" that retains immunomodulatory and antimicrobial properties while lacking pigment-inducing activity.[7][8]

      A critical mechanistic distinction: KPV does not bind melanocortin receptors (MC1R-MC5R) in mammalian cells, does not increase cAMP, and does not induce melanogenesis. Instead, it enters cells via the PepT1 (SLC15A1) oligopeptide transporter — which is notably upregulated in inflamed colonic tissue — enabling targeted delivery to sites of active inflammation.[3][4]

      The FDA placed KPV on the Category 2 Bulk Drug Substances list, citing insufficient human exposure data and potential immunogenicity from peptide-related impurities.[5] No large-scale randomized controlled trials have been published; human data is limited to patent case studies (psoriasis, contact dermatitis).[9]

**Mechanism of Action:**

### Mechanism of Action

      #### PepT1-Mediated Cellular Entry (Primary Mechanism)

      Unlike its parent α-MSH — which acts through G-protein coupled melanocortin receptors (MC1R–MC5R) — KPV enters cells via the proton-coupled oligopeptide transporter PepT1 (SLC15A1). In human intestinal epithelial cells (Caco2-BBE), PepT1 transports KPV with a Km of ~160 µM; in Jurkat T-cells, Km ≈ 700 µM.[3][4]

      #### Importin-α3 Binding (Intracellular Target)

      Once internalized, KPV binds Importin-α3 (Imp-α3) at armadillo domains 7–8, physically blocking the nuclear import of NF-κB p65RelA — preventing it from entering the nucleus to transcribe pro-inflammatory genes.[10][11]

      #### NF-κB Pathway Inhibition (Dual Mechanism)

      KPV inhibits NF-κB through two complementary actions: (1) stabilizing IκBα by preventing its phosphorylation and degradation, and (2) blocking p65RelA nuclear translocation via Importin-α3 binding. This dual mechanism provides robust suppression of inflammatory gene transcription at concentrations as low as 10 nM.[10][12]

      #### MAPK Pathway Inhibition

      KPV inhibits phosphorylation and activation of three major MAP kinases: ERK1/2, JNK, and p38 — reducing pro-inflammatory cytokine production induced by TNFα and other stimuli.[13]

      #### mTORC1 Activation

      KPV activates mTORC1 (mechanistic target of rapamycin complex 1), evidenced by increased phosphorylation of p70 S6K at T389 — suggesting a role in translational control and cell growth recovery during inflammation.[14]

      #### Calcium Signaling (Keratinocytes)

      In human keratinocytes, KPV elevates intracellular Ca²⁺ concentrations via an adenosine agonist-dependent pathway — distinct from the cAMP pathway used by α-MSH in other tissues.[14]

      #### α-MSH vs. KPV: Key Distinctions

      
        Featureα-MSH (Parent)KPV (Fragment)
        
          Structure13 amino acids (tridecapeptide)3 amino acids (C-terminal tripeptide)
          Primary EntryBinds MC1R–MC5R (cell surface)Transported by PepT1 (intracellular)
          Second MessengerIncreases cAMPDoes NOT increase cAMP; ↑ Ca²⁺ in keratinocytes
          PigmentationInduces melanogenesisNo pigmentation effect
          InflammationInhibits IκBα degradationInhibits IκBα + blocks p65 nuclear import via Importin-α3

**Research Applications:**

### Research Applications

      KPV demonstrates potent anti-inflammatory activity across diverse tissue models, with unusually favorable therapeutic index given its nanomolar potency:

      
        - Inflammatory Bowel Disease / Colitis — Oral KPV in drinking water reduces DSS/TNBS-induced colitis (MPO reduced ~50%, weight loss attenuated). HA-nanoparticle delivery achieves 12,000-fold potency increase over free peptide. PepT1-dependent mechanism confirmed in KO mice.[3][6][15]

        - Dermatological Inflammation — Topical KPV reduces psoriasis symptoms (>8 hours relief vs 3 hours hydrocortisone), atopic/contact dermatitis without skin atrophy or steroid side effects. Patent case studies document human efficacy.[9][16]

        - Corneal and Cutaneous Wound Healing — Accelerated re-epithelialization in rabbit corneal wounds (topical, 4x daily) and oral mucositis (KPV@PPP_E hydrogel) with tissue morphology restoration.[17][18]

        - Antimicrobial Activity — Active against S. aureus and C. albicans at picomolar to micromolar range. Dimeric form [CKPV]₂ shows enhanced candidacidal activity.[19][20]

        - Arthritis and Joint Inflammation — Reduced joint swelling, cartilage destruction, and PMN leukocyte infiltration in crystal-induced peritonitis models.[21]

        - Pulmonary Inflammation — Inhibits MMP-9 activity, reduces eotaxin and IL-8 secretion in bronchial epithelial cells exposed to TNFα or RSV.[22]

        - Colitis-Associated Cancer — KPV prevented AOM/DSS-induced carcinogenesis in WT mice but not PepT1-KO mice, confirming PepT1-dependent anti-tumorigenic mechanism.[23]

        - Vascular Calcification — Self-assembled KPV/rapamycin nanodrugs inhibit vascular calcification via anti-inflammatory + autophagy pathways.[24]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Dalmasso et al. (2008)C57BL/6 mice — DSS + TNBS colitis100 µM KPV oral: MPO reduced ~50% (DSS); weight loss 5–10% vs 15–20% control (p [3]
          Kannengiesser et al. (2008)Mice — DSS + MC1R-KOKPV rescued MC1Re/e mice from death in DSS colitis → mechanism is MC1R-independent[15]
          Xiao et al. (2017)FVB mice — HA-KPV-NPs oral16 µg/kg/day × 6 days: 12,000-fold lower dose vs free KPV with equivalent efficacy; MPO to healthy-control levels (p [6]
          Viennois et al. (2016)WT/PepT1-KO mice — AOM/DSSKPV prevented colitis-associated cancer in WT but NOT PepT1-KO → PepT1 dependence confirmed for anti-tumorigenic effects[23]
          Bonfiglio et al. (2006)Rabbits — corneal woundsTopical KPV 4x daily × 4 days: significantly smaller corneal wounds vs control[17]
          Shao et al. (2022)Rats — oral mucositis + MRSAKPV@PPP_E hydrogel: ↓ IL-1β, TNF-α; ↑ IL-10; restored gingival tissue morphology; dual anti-inflammatory + antibacterial[18]
        
      

      #### Human Data (Patent Case Studies)

      
        Casen=ResultRef
        
          Psoriasis (US 6,894,028)11 mg topical KPV: symptom relief >8 hours/application (vs 3 hours hydrocortisone); no AEs (hydrocortisone → telangiectasia/atrophy)[9]
          Contact Dermatitis (US 6,894,028)1Topical KPV: marked improvement within minutes; symptoms did not return[9]
        
      

      #### Dose-Response Parameters

      
        ParameterValueRef
        
          Anti-inflammatory IC (NF-κB/MAPK)10 nM[3]
          Antimicrobial rangePicomolar to micromolar[19]
          PepT1 Km (intestinal cells)~160 µM[3]
          PepT1 Km (T-cells)~700 µM[4]
          Oral dose (murine colitis)100 µM in drinking water[3]
          HA-NP dose (12,000x potency)16 µg/kg/day oral[6]
          Plasma half-life[25]
          Acute toxicity (LD50)Not identified (>100 mg/kg)[25]
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (26 references):**

- Sikiric P, et al. A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis. Journal of Physiology-Paris. 1993;87(5):313-327. — https://doi.org/10.1016/0928-4257(93)90038-U
- Brzoska T, Luger TA, Maaser C, Abels C, Böhm M. Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives. Endocrine Reviews. 2008;29(5):581-602. — https://doi.org/10.1210/er.2007-0027
- Dalmasso G, Charrier-Hisamuddin L, Nguyen HTT, Yan Y, Sitaraman S, Merlin D. PepT1-Mediated Tripeptide KPV Uptake Reduces Intestinal Inflammation. Gastroenterology. 2008;134(1):166-178. — https://doi.org/10.1053/j.gastro.2007.10.026
- Laroui H, Dalmasso G, Nguyen HT, Yan Y, Sitaraman SV, Merlin D. Drug-loaded nanoparticles targeted to the colon with polysaccharide hydrogel reduce colitis in a mouse model. Gastroenterology. 2010;138:843-853. — https://doi.org/10.1053/j.gastro.2009.11.003
- U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. FDA.gov. Updated 2023. — https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding
- Xiao B, Xu Z, Viennois E, Zhang Y, Zhang Z, Zhang M, Han MK, Kang Y, Merlin D. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Molecular Therapy. 2017;25(7):1628-1640. — https://doi.org/10.1016/j.ymthe.2016.11.020
- Hiltz ME, Lipton JM. Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH. FASEB Journal. 1989;3:2282-2284. — https://doi.org/10.1096/fasebj.3.11.2550304
- Luger TA, Brzoska T. α-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. Annals of the Rheumatic Diseases. 2007;66(Suppl 3):iii52-iii55. — https://doi.org/10.1136/ard.2007.079780
- Lipton JM, Catania AP. Use of KPV tripeptide for dermatological disorders. U.S. Patent No. 6,894,028 B2. 2005. — https://patents.google.com/patent/US6894028B2
- Getting SJ, Schiöth HB, Perretti M. Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides. Journal of Pharmacology and Experimental Therapeutics. 2003;306(2):631-637. — https://doi.org/10.1124/jpet.103.051623
- Kelly JM, Moir AJG, Carlson KE, Haycock JW. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity. Peptides. 2006;27(3):431-437. — https://doi.org/10.1016/j.peptides.2005.01.026
- Land SC. Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides. International Journal of Physiology, Pathophysiology and Pharmacology. 2012;4(2):59-73. — https://pubmed.ncbi.nlm.nih.gov/22745921/
- Elliott RJ, Szabo M, Wagner MJ, Kemp EH, MacNeil S, Haycock JW. alpha-Melanocyte-stimulating hormone, MSH 11-13 KPV and adrenocorticotropic hormone signalling in human keratinocyte cells. Journal of Investigative Dermatology. 2004;122(4):1010-1019. — https://doi.org/10.1111/j.0022-202X.2004.22413.x
- Songok AC, Panta P, Doerrler WT, Macnaughtan MA, Taylor CM. Structural modification of the tripeptide KPV by reductive glycoalkylation of the lysine residue. PLOS One. 2018;13(6):e0199686. — https://doi.org/10.1371/journal.pone.0199686
- Kannengiesser K, Maaser C, Heidemann J, et al. Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease. Inflammatory Bowel Diseases. 2008;14(3):324-331. — https://doi.org/10.1002/ibd.20334
- Böhm M, Luger T. Are melanocortin peptides future therapeutics for cutaneous wound healing? Experimental Dermatology. 2019;28:219-224. — https://doi.org/10.1111/exd.13867
- Bonfiglio V, et al. Effects of the COOH-terminal tripeptide alpha-MSH(11-13) on corneal epithelial wound healing: role of nitric oxide. Experimental Eye Research. 2006;83(6):1366-1372. — https://doi.org/10.1016/j.exer.2006.07.014
- Shao W, Chen R, Lin G, Ran K, Zhang Y, Yang J, Xu H. In situ mucoadhesive hydrogel capturing tripeptide KPV: the anti-inflammatory, antibacterial and repairing effect on chemotherapy-induced oral mucositis. Biomaterials Science. 2022;10:227-242. — https://doi.org/10.1039/D1BM01466H
- Cutuli M, Cristiani S, Lipton JM, Catania A. Antimicrobial effects of alpha-MSH peptides. Journal of Leukocyte Biology. 2000;67(2):233-239. — https://doi.org/10.1002/jlb.67.2.233
- Catania A, et al. Three-dimensional structure of the α-MSH-derived candidacidal peptide [Ac-CKPV]2. The Journal of Peptide Research. 2005;66(1):19-26. — https://doi.org/10.1111/j.1399-3011.2005.00265.x
- Charnley M, Moir AJG, Douglas CWI, Haycock JW. Anti-microbial action of melanocortin peptides and identification of a novel X-Pro-d/l-Val sequence in Gram-positive and Gram-negative bacteria. Peptides. 2008;29(6):1004-1009. — https://doi.org/10.1016/j.peptides.2008.02.003
- Land SC, et al. KPV inhibits MMP-9 activity and reduces eotaxin and IL-8 secretion in bronchial epithelial cells. International Journal of Physiology, Pathophysiology and Pharmacology. 2012;4(2):59-73. — https://pubmed.ncbi.nlm.nih.gov/22745921/
- Viennois E, et al. Critical Role of PepT1 in Promoting Colitis-Associated Cancer and Therapeutic Benefits of the Anti-inflammatory PepT1-Mediated Tripeptide KPV in a Murine Model. Cellular and Molecular Gastroenterology and Hepatology. 2016;2(3):340-357. — https://doi.org/10.1016/j.jcmgh.2016.01.006
- Wu Y, et al. KPV and RAPA Self-Assembled into Carrier-Free Nanodrugs for Vascular Calcification Therapy. Advanced Healthcare Materials. 2024. — https://pubmed.ncbi.nlm.nih.gov/
- Catania A, et al. Inhibitory effects of the peptide (CKPV)2 on endotoxin-induced host reactions. The Journal of Surgical Research. 2006;131. — https://pubmed.ncbi.nlm.nih.gov/
- Pawar K, Kolli CS, Rangari NS, Babu RJ. Transdermal Iontophoretic Delivery of Lysine-Proline-Valine (KPV) Peptide Across Microporated Human Skin. Journal of Pharmaceutical Sciences. 2017;106(7):1814-1820. — https://doi.org/10.1016/j.xphs.2017.03.015

**Storage & Handling:**

Store lyophilized KPV at −20°C for 2–3 years; reconstituted at 2–8°C for 7–14 days. Avoid freeze-thaw cycles. Protect from light/moisture.

**Author:** Dr. James M. Lipton
James M. Lipton, PhD, is a pioneering researcher affiliated with Zengen Inc. and the University of Texas. Lipton is the lead inventor who established that the anti-inflammatory and antipyretic activities of the larger α-MSH hormone reside specifically in its C-terminal tripeptide sequence, KPV. He d

---

### Ll 37

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₂₀₅H₃₄₀N₆₀O₅₃ |
| Molecular Weight | 4493.33 Da |
| CAS Number | Not established |
| PubChem CID | 16198951 |
| Sequence (1-letter) | LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES |
| Sequence (3-letter) | Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser |
| Structure | Linear, amphipathic α-helix (in membranes), cysteine-free, curved helix-bend-helix motif (residues 2–31) |
| Net Charge | +6 at physiological pH |
| Gene Origin | CAMP gene, chromosome 3p21.3 — encodes hCAP18 precursor |
| Classification | Cathelicidin Antimicrobial Peptide / Host Defense Peptide |
| Clinical Name | Ropocamptide (Promore Pharma AB) |

**Identifiers:**
- Purity Standard: ≥90–110% content by HPLC (UV at 217 nm)
- Identity Confirmation: LC-MS molecular mass ~4493.33 Da
- Counter-Ion: Acetate (synthetic peptide acetate salt via SPPS)
- Detection Methods: RP-HPLC, LC-MS, amino acid analysis, ELISA, antimicrobial bioassays

**Overview:**

### Overview

      LL-37 is a 37-residue cationic antimicrobial peptide (AMP) and the only member of the cathelicidin family identified in humans. Its amino acid sequence is LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES.[1]

      Parent molecule: LL-37 is derived from a larger, inactive precursor protein called hCAP18 (human Cationic Antimicrobial Protein, 18 kDa). The CAMP gene on chromosome 3p21.3 encodes hCAP18. The active LL-37 peptide is released extracellularly through proteolytic cleavage — primarily by proteinase 3 in neutrophils and kallikreins (K5/K7) in keratinocytes.[2]

      Cellular origin: Constitutively expressed or induced in neutrophils (stored in specific granules), monocytes, mast cells, and epithelial cells of the skin, gastrointestinal tract, and respiratory tract.[3]

      Structurally, LL-37 is a linear, amphipathic peptide (MW 4493.33 Da) with a net charge of +6 at physiological pH. It is cysteine-free and adopts an α-helical structure in membrane environments but remains disordered in aqueous solution. NMR studies reveal a curved helix-bend-helix motif spanning residues 2–31 with a disordered C-terminal tail.[1]

      LL-37 expression in the skin is regulated by Vitamin D. Abnormal LL-37 levels are linked to psoriasis (overexpression) and atopic dermatitis (suppression).[6]

**Mechanism of Action:**

### Mechanism of Action

      #### Primary Antimicrobial: "Carpet-Like" Membrane Disruption

      LL-37 disrupts bacterial membranes via electrostatic attraction to anionic bacterial surfaces → hydrophobic insertion → toroidal pore formation or micellization ("carpet-like" mechanism). It acts preferentially on Gram-negative bacteria but is effective against both Gram-positive and drug-resistant strains. Eukaryotic membranes are protected by high cholesterol content.[3][7]

      #### Receptor Targets

      
        ReceptorTypeFunctional Effect
        
          FPR2/FPRL1GPCRChemotaxis of neutrophils, monocytes, T cells (Yang et al., 2000)[8]
          P2X7PurinergicIL-1β processing; neutrophil survival (Elssner et al., 2004)[8]
          EGFRReceptor Tyrosine KinaseTransactivation → keratinocyte migration → wound healing (Tokumaru et al., 2005)[9]
          IGF-1RReceptor Tyrosine KinasePartial agonist → proliferation (Girnita et al., 2012)[10]
          CXCR2ChemokineFunctional ligand on neutrophils (Zhang et al., 2009)[8]
          MrgX2GPCRMast cell degranulation (Subramanian et al., 2011)[8]
          TLR9Toll-like ReceptorDNA-LL-37 complexes trigger endosomal TLR9 (Lande et al., 2007)[10]
        
      

      #### Downstream Signaling Cascades

      
        - ERK1/2 and p38 MAPK: Crucial for keratinocyte migration and wound healing; modulates cytokine production in monocytes.[9]

        - PI3K/Akt → CREB: Cell survival signaling via P2X7–SFK–Akt pathway in keratinocytes.[9]

        - mTOR: Activation suppresses autophagy in pancreatic cancer → ROS accumulation → DNA damage.[11]

        - NF-κB: Inhibits p50/p65 translocation in inflammation (anti-inflammatory); may activate in some cancers (context-dependent).[8]

      

      #### Anti-Biofilm Activity

      Inhibits quorum-sensing (Las/Rhl systems) and promotes twitching motility; effective at sub-MIC concentrations (0.5 µg/mL) — far below bactericidal thresholds.[7]

      #### LPS Neutralization

      Binds and neutralizes lipopolysaccharide (LPS), preventing endotoxin-induced macrophage activation and cytokine storm.[12]

      #### Biphasic Dose-Response

      LL-37 exhibits a distinct bell-shaped dose response: ≤1 µM = anti-apoptotic, pro-healing; >10 µM = cytotoxic. In clinical trials, 0.5 mg/mL was 6-fold more effective than placebo, while the highest dose (3.2 mg/mL) showed no improvement.[5]

      #### vs. Related Compounds

      
        CompoundKey Difference
        
          hCAP18Inactive 18 kDa precursor; LL-37 is the active C-terminal domain released by proteolysis
          KR-12Truncated fragment (residues 18–29); retains antimicrobial activity with less cytotoxicity
          D-LL-37Protease-resistant enantiomer; retains antimicrobial and anti-biofilm activity
          CRAMP (mouse)Murine ortholog; functional homology but non-identical sequence

**Research Applications:**

### Research Applications

      LL-37 research spans antimicrobial resistance, wound healing, oncology, and immunology across 8+ indication categories:

      
        - Chronic Wound Healing — Promotes granulation tissue, re-epithelialization, and angiogenesis in venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs).[5][13]

        - Antimicrobial Resistance — Broad-spectrum activity against MDR bacteria; anti-biofilm; synergy with conventional antibiotics (azithromycin, colistin, ciprofloxacin, vancomycin).[7]

        - Oncology (Dual Role) — Anti-tumorigenic: colon, gastric, and pancreatic cancer (apoptosis, autophagy suppression, immune reprogramming). Pro-tumorigenic: breast, lung, ovarian, and melanoma (context-dependent).[11][10]

        - Antiviral Research — RSV, Influenza A, HSV-1, HIV-1 — disrupts viral envelopes and blocks entry.[3]

        - Antifungal Research — Active against Candida albicans and Cryptococcus neoformans via membrane permeabilization.[3]

        - Sepsis/Endotoxemia — LPS neutralization prevents endotoxin-induced macrophage activation and cytokine storms.[12]

        - Bone Regeneration — Stimulates proliferation and osteogenic differentiation of BMSCs; recruits MSCs to injury sites.[14]

        - Drug Delivery Systems — Lipid nanoparticles, chitosan nanoparticles, hydrogels for improved stability and reduced cytotoxicity.[15]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Zhang et al. (2022)C57/BL6 mice, Pan02 PDAC — 20 mg/kg/day IP × 14d42% reduction in tumor growth (p[11]
          Overhage et al. (2008)P. aeruginosa biofilm — 0.5 µg/mLInhibits biofilm formation via quorum-sensing downregulation (Las/Rhl); promotes twitching motility at sub-MIC[7]
          Wu et al. (2010)Colon cancer cellsLL-37 inhibits proteasome → activates BMP signaling → p21Waf1 → cell cycle arrest[10]
          Koczulla et al. (2003)Dexamethasone-treated mice — topical LL-37Increased vascularization and re-epithelialization; key role in wound regeneration via angiogenesis[9]
          Beaumont et al. (2014)Bone marrow stromal cellsStimulates proliferation and osteogenic differentiation of BMSCs; recruits MSCs to injury sites[14]
          Tuberculosis (in vivo)M. tuberculosis mice — ~1 mg/kg IT 3x/wk × 28d3–10 fold reduction in lung bacilli; effective against drug-sensitive and MDR strains[7]
        
      

      #### Clinical Trials

      
        TrialPopulationInterventionKey ResultsRef
        
          Phase IIb VLUn=148Topical 0.5 mg/mL, 3x/wk × 13 wkTotal population: NS. Subgroup (ulcers ≥10 cm²): 28.1% vs 8.1% closure (p=0.0458); healing rate 0.0367/day vs 0.0093/day (p=0.0439)[16]
          Phase I/II VLUn=34Topical 0.5/1.6/3.2 mg/mL, 2x/wk × 4 wk0.5 mg/mL healing rate 6-fold higher than placebo (p=0.003); ulcer area ↓ 68%; bell-shaped dose-response[5]
          RCT — DFUn=25LL-37 cream 0.5 mg/g, 2x/wk × 4 wkGranulation index significantly ↑ days 7–28 (p11/13 vs 3/12 achieved >0.41 increase; no effect on bacterial load[13]
          Phase I Melanoman=36 plannedIntratumoral 250–2000 µg/tumor, weekly × 8 wkAcceptable tolerability; variable biological response; dermatologic toxicity noted[17]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          ClinicalSafe and well-tolerated in 148-patient Phase IIb; no systemic safety concerns; mild local reactions (redness, edema)
          Dose-Dependent3.2 mg/mL → increased local reactions; bell-shaped dose-response
          Cytotoxicity>13–25 µM towards eukaryotic cells; significantly inhibited by serum
          Cancer RiskContext-dependent: anti-tumorigenic in colon/gastric/pancreatic; pro-tumorigenic in breast/lung/ovarian/melanoma
          Drug InteractionsSynergy with antibiotics (azithromycin, colistin, vancomycin); inhibited by glycosaminoglycans; Vitamin D upregulates expression
          StabilitySusceptible to protease degradation; short plasma half-life; D-LL-37 enantiomer is protease-resistant
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Johansson J, Gudmundsson GH, Rottenberg ME, et al. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. Journal of Biological Chemistry. 1998;273(6):3718-3724. — https://pubmed.ncbi.nlm.nih.gov/9452491/
- Gudmundsson GH, Agerberth B, Odeberg J, et al. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. European Journal of Biochemistry. 1996;238(2):325-332. — https://pubmed.ncbi.nlm.nih.gov/8681941/
- Ridyard KE, Overhage J. The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent. Antibiotics. 2021;10(6):650. — https://doi.org/10.3390/antibiotics10060650
- Duplantier AJ, van Hoek ML. The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds. Frontiers in Immunology. 2013;4:143. — https://doi.org/10.3389/fimmu.2013.00143
- Grönberg A, Mahlapuu M, Ståhle M, et al. Treatment with LL-37 is Safe and Effective in Enhancing Healing of Hard-to-Heal Venous Leg Ulcers: A Randomized, Placebo-Controlled Clinical Trial. Wound Repair and Regeneration. 2014;22(5):613-621. — https://doi.org/10.1111/wrr.12211
- Yang B, Good D, Mosaiab T, et al. Significance of LL-37 on Immunomodulation and Disease Outcome. BioMed Research International. 2020;2020:8349712. — https://doi.org/10.1155/2020/8349712
- Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. Journal of Investigative Dermatology. 2003;120(3):379-389. — https://doi.org/10.1046/j.1523-1747.2003.12069.x
- Scott MG, Davidson DJ, Gold MR, et al. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. The Journal of Immunology. 2002;169(7):3883-3891. — https://doi.org/10.4049/jimmunol.169.7.3883
- Svensson D, Nilsson BO. Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update. Inflammation Research. 2025;74(1):36. — https://doi.org/10.1007/s00011-025-02005-8
- Piktel E, Niemirowicz K, Wnorowska U, et al. The Role of Cathelicidin LL-37 in Cancer Development. Archivum Immunologiae et Therapiae Experimentalis. 2016;64(1):33-46. — https://doi.org/10.1007/s00005-015-0359-5
- Zhang Z, Chen WQ, Zhang SQ, et al. The human cathelicidin peptide LL-37 inhibits pancreatic cancer growth by suppressing autophagy and reprogramming of the tumor immune microenvironment. Frontiers in Pharmacology. 2022;13:906625. — https://doi.org/10.3389/fphar.2022.906625
- Lu F, Zhu Y, Zhang G, Liu Z. Renovation as innovation: Repurposing human antibacterial peptide LL-37 for cancer therapy. Frontiers in Pharmacology. 2022;13:944147. — https://doi.org/10.3389/fphar.2022.944147
- Miranda E, Bramono K, Yunir E, et al. Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Archives of Dermatological Research. 2023;315(9):2623-2633. — https://doi.org/10.1007/s00403-023-02657-8
- Seil M, Nagant C, Dehaye JP, et al. Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties. Pharmaceuticals. 2010;3(11):3435-3460. — https://doi.org/10.3390/ph3113435
- Ergün FC, Kars MD, Kars G. Development and Characterization of LL37 Antimicrobial-Peptide-Loaded Chitosan Nanoparticles. Polymers. 2025;17(13):1884. — https://doi.org/10.3390/polym17131884
- Mahlapuu M, Sidorowicz A, Mikosinski J, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial. Wound Repair and Regeneration. 2021;29(6):938-950. — https://doi.org/10.1111/wrr.12977
- Ohuchi K, Ikawa T, Amagai R, et al. LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages. Cancers. 2023;15(6):1678. — https://doi.org/10.3390/cancers15061678
- Miura S, Garcet S, Li X, et al. Cathelicidin Antimicrobial Peptide LL37 Induces Toll-Like Receptor 8 and Amplifies IL-36γ and IL-17C in Human Keratinocytes. Journal of Investigative Dermatology. 2023;143(5):832-841.e4. — https://doi.org/10.1016/j.jid.2022.10.017
- Lin X, Wang R, Mai S. Advances in delivery systems for the therapeutic application of LL37. Journal of Drug Delivery Science and Technology. 2020;60(9):102016. — https://doi.org/10.1016/j.jddst.2020.102016
- Wu WK, Wang G, Coffelt SB, et al. Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications. International Journal of Cancer. 2010;127(8):1741-1747. — https://doi.org/10.1002/ijc.25489
- Alalwani SM, Sierigk J, Herr C, et al. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. European Journal of Immunology. 2010;40(4):1118-1126. — https://doi.org/10.1002/eji.200939275
- Lozeau LD, Kole D, Dominko T, et al. Activity and toxicity of a recombinant LL37 antimicrobial peptide. Frontiers in Bioengineering and Biotechnology. 2016. — https://doi.org/10.3389/conf.FBIOE.2016.01.02255
- Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36. — https://doi.org/10.1186/s12967-023-03885-2
- M.D. Anderson Cancer Center. Induction of Antitumor Response in Melanoma Patients Using the Antimicrobial Peptide LL37. ClinicalTrials.gov Protocol NCT02225366. 2015. — https://clinicaltrials.gov/ct2/show/NCT02225366

**Storage & Handling:**

Lyophilized powder/concentrate stored at -20°C. Cream formulation stable >99 months at 4°C, >75 months at 28°C (melts at 40°C). Reconstituted solutions should be used immediately or frozen.

**Author:** Dr. Gudmundur Hrafn Gudmundsson
Gudmundur Hrafn Gudmundsson is a Professor at the University of Iceland and Karolinska Institutet (Sweden). He played a foundational role in the discovery of LL-37, cloning the FALL-39 gene and isolating the mature peptide from human neutrophils. His work established the processing mechanism of the 

---

### Melanotan 2

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₅₀H₆₉N₁₅O₉ |
| Molecular Weight | 1024.18 Da |
| CAS Number | 121062-08-6 |
| PubChem CID | 92432 |
| Sequence | Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂ |
| Structure | Cyclic heptapeptide; lactam bridge (Asp-Lys); Ac-Nle replaces α-MSH Ser-Tyr-Ser-Met; D-Phe replaces L-Phe |
| Parent Molecule | α-MSH (alpha-melanocyte-stimulating hormone) |
| InChI Key | JDKLPDJLXHXHNV-MFVUMRCOSA-N |
| Half-Life (Human) | ~1–2 hours (enhanced vs α-MSH by cyclic structure) |
| BBB Penetration | Yes (unlike Melanotan I) |
| Receptor Profile | Non-selective MCR agonist: MC1R, MC3R (Ki 1.3 nM), MC4R (Ki 1.1 nM), MC5R; NO activity at MC2R |

**Identifiers:**
- Purity Standard: ≥98% by RP-HPLC
- Identity Confirmation: ESI-MS m/z 512 [M+2H]²⁺ and 1024 [M+H]⁺; LC-UV-MS/MS validated
- Counter-Ion: Acetate (TFA-free)
- Synonyms: MT-II, MT2, Melanotan-II, Barbie drug/peptide
- Detection Methods: HPLC, ESI-MS, LC-UV-MS/MS, urine/blood MS (toxicology)

**Overview:**

### Overview

      Melanotan II (MT-II) is a synthetic, cyclic heptapeptide analog of the endogenous 13-amino-acid hormone α-melanocyte-stimulating hormone (α-MSH). It was originally synthesized at the University of Arizona in the late 1980s by Victor Hruby, Mac Hadley, and Robert Dorr.[1]

      Chemically, MT-II is defined as Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂, a shortened variant of α-MSH with key modifications: a lactam bridge cyclization (Asp→Lys) increases enzymatic resistance, and D-Phenylalanine substitution enhances potency. These make MT-II "superpotent" compared to native α-MSH and enable it to cross the blood-brain barrier — a key distinction from the linear Melanotan I (afamelanotide).[1][3]

      MT-II acts as a non-selective agonist at melanocortin receptors MC1R, MC3R, MC4R, and MC5R with high nanomolar affinity (Ki ~1.1–1.3 nM), but does NOT bind MC2R (the ACTH receptor). This broad receptor activation drives its diverse effects — tanning, erectogenic, anorexigenic, and social behavioral modulation.[2]

      The active metabolite of MT-II — Bremelanotide (PT-141) — was FDA-approved in 2019 under the brand name Vyleesi for hypoactive sexual desire disorder in premenopausal women. MT-II itself remains unapproved by any regulatory body.[3]

**Mechanism of Action:**

### Mechanism of Action

      #### Melanocortin Receptor Binding

      MT-II is a non-selective agonist at four of five melanocortin receptors (MCRs), all members of the GPCR superfamily:

      
        ReceptorPrimary LocationFunction When ActivatedAffinity
        
          MC1RMelanocytes (skin)Eumelanin synthesis → tanning/photoprotectionHigh
          MC3RHypothalamus, NAccEnergy homeostasis, feeding behaviorKi ~1.3 nM
          MC4RHypothalamus (PVN), spinal cordErectile function, appetite suppression, thermogenesisKi ~1.1 nM
          MC5RExocrine glands, lymphocytesSebum production, immune modulationModerate
          MC2RAdrenal cortexACTH receptor — NO MT-II bindingNone
        
      

      #### Primary Signaling: cAMP-PKA Pathway

      Upon MCR binding, MT-II activates Gs-coupled adenylate cyclase → increased intracellular cAMP → PKA activation:[2]

      
        - Melanogenesis (MC1R): PKA → CREB phosphorylation → MITF transcription → tyrosinase upregulation → eumelanin production

        - Erectile function (MC4R/CNS): Hypothalamic PVN activation → dopaminergic/oxytocinergic downstream → neuronal NO release → intracavernosal pressure increase[5]

        - Appetite suppression (MC3R/MC4R): Hypothalamic MCR activation → reduced food intake + increased thermogenesis[6]

        - Social behavior (MC4R): Selective nucleus accumbens activation → oxytocin-dependent social learning[7]

      

      #### Off-Target: Mast Cell Activation

      MT-II cross-reacts with MRGPRB2/MRGPRX2 receptors on mast cells, causing pseudo-allergic histamine release → H1 receptor activation → hypothermia (in mice). Subcutaneous dosing reduces histamine release by 63% vs. intraperitoneal.[8]

      #### vs. Related Compounds

      
        CompoundStructureBBBKey Difference
        
          MT-IICyclic heptapeptideYesNon-selective MCR agonist; tanning + erectogenic + anorexigenic
          Melanotan I (Afamelanotide)Linear [Nle⁴,D-Phe⁷]-α-MSHNoTanning only (peripheral MC1R); no CNS effects; TGA/EMA approved for EPP
          Bremelanotide (PT-141)Deaminated MT-II metaboliteYesFDA-approved (Vyleesi) for HSDD; reduced tanning activity
          α-MSH (native)Linear tridecapeptideLimitedShort half-life; rapidly degraded; weak potency

**Research Applications:**

### Research Applications

      Melanotan II research spans dermatology, sexual medicine, neuroendocrinology, oncology, and behavioral neuroscience across 7+ indication categories:

      
        - Skin Pigmentation & Photoprotection — MC1R stimulation → eumelanin synthesis → tanning without UV exposure; as few as 5 low doses induced visible tanning in Phase I trials.[1]

        - Sexual Dysfunction — 80% of men with psychogenic ED achieved clinically apparent erections (0.025 mg/kg SC); tip rigidity >80% for 38 min vs 3 min placebo (p=0.0045); enhanced proceptive behaviors in female rats.[3][9]

        - Metabolic Regulation & Obesity — Central MC3R/MC4R activation: intraabdominal fat -35% (low dose) to -55% (high dose); iBAT thermogenesis 3-fold increase; appetite suppression via NAcc.[6][10]

        - Autism & Social Behavior — Sociability index increased from 3.1 to 26.3 (p[11][7]

        - Neuroprotection & Nerve Regeneration — 20 µg/kg SC every 48h enhanced sensory function recovery in rat sciatic nerve crush model.[12]

        - Addiction Research — Synergistic augmentation of naltrexone to reduce binge-like ethanol intake in mice.[13]

        - Oncology — Topical MT-II suppressed melanoma tumor growth via MC1R → PTEN upregulation + COX-2/PGE2 inhibition; systemic use carries melanoma risk.[14]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Côté et al. (2017)F344BN rats — ICV 0.04–1 µg/day × 40dFat pads -35% to -55% (p3-fold ↑; food intake returned to normal by day 5 — weight loss via ↑ energy expenditure[6]
          Vemulapalli et al. (2001)NZW rabbits — 66–133 µg/kg IVCavernosal pressure 3.2-fold ↑ (p[5]
          Minakova et al. (2019)MIA autism-model mice — ICV 2.5 µg/day × 7dSociability index 3.1 → 26.3 (p[11]
          Ford et al. (2024)Prairie voles (WT vs Oxtr-KO) — IP/ICVSocial context → NAcc Fos ↑ (p in WT but NOT Oxtr-KO; non-social → PVN activation only → oxytocin-dependent social learning mechanism[7]
          Jain et al. (2018)C57BL/6J mice — 10 mg/kg IPPlasma histamine 4-fold ↑ (p[8]
          Eliason et al. (2022)C57BL/6J mice — NAcc microinjectionAll doses ↓ food intake at 1,2,4,6h (p[10]
          Wu et al. (2020)B16-F10 melanoma mice — topicalDramatically slowed tumor growth; ↑PTEN, ↓COX-2/PGE2, induced cell death; inhibited migration/invasion[14]
        
      

      #### Human Clinical Data

      
        StudyPopulationKey ResultsRef
        
          Dorr et al. (1996) — Phase In=3 healthy males; 0.01–0.025 mg/kg SCVisible tanning in 2/3 subjects; spontaneous erections 1–5h post-dose; mild nausea; recommended Phase I dose: 0.025 mg/kg[1]
          Wessells et al. (1998) — Psychogenic EDn=10 men; 0.025 mg/kg SC, double-blind crossover80% response rate; tip rigidity >80% for 38 min vs 3 min placebo (p=0.0045)[3]
          Wessells et al. (2000) — Organic EDn=10 men; 0.025 mg/kg SC, double-blind crossover63% erection rate (12/19 injections vs 1/21 placebo); tip rigidity >80% for 45.3 min vs 1.9 min (p=0.047); enhanced sexual desire[9]
        
      

      #### Safety Concerns — Case Reports (Unregulated Use)

      
        EventDetailsRef
        
          Priapism22-hour painful erection (unknown dose); 60-year-old required surgical shunting after 10 mg injection[15]
          Rhabdomyolysis39-year-old male: 6 mg SC → CPK 17,773 IU/L; tachycardia, hypertension, agitation, renal dysfunction[16]
          Renal Infarction45-year-old male: 50% right kidney infarction after 10 mg injections; likely sympathomimetic vasoconstriction[17]
          Melanoma/Nevi Changes16-year-old female (FAMMM): darkened/enlarged nevi + dysplastic nevus after 2 months (0.5 mg/day); melanoma in situ reports[18]
          Common Side EffectsNausea (dose-dependent), facial flushing, fatigue, yawning/stretching, decreased appetite, darkened moles[1]
        
      

      #### Pharmacokinetics & Dosing Summary

      
        ParameterValue
        
          Human Half-Life~1–2 hours (enhanced vs α-MSH by cyclic structure)
          BBB PenetrationYes (unlike Melanotan I)
          Active MetaboliteBremelanotide (PT-141) — deaminated, lacks C-terminal amide
          ED Research Dose0.025 mg/kg SC (Phase I optimal for erection with manageable side effects)
          ContraindicationsCardiovascular disease; personal/family melanoma history; PDE5 inhibitor combination (priapism risk)
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sciences. 1996;58(20):1777-1784. — https://doi.org/10.1016/0024-3205(96)00160-9
- Hadley ME, Dorr RT. Melanocortin peptide therapeutics: Historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930. — https://pubmed.ncbi.nlm.nih.gov/
- Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: Double-blind, placebo controlled crossover study. The Journal of Urology. 1998;160(2):389-393. — https://pubmed.ncbi.nlm.nih.gov/9679893/
- FDA Warning Letters regarding unauthorized marketing of Melanotan products. — https://www.fda.gov/
- Vemulapalli R, Kurowski S, Salisbury B, et al. Activation of central melanocortin receptors by MT-II increases cavernosal pressure in rabbits by the neuronal release of NO. British Journal of Pharmacology. 2001;134(8):1705-1710. — https://doi.org/10.1038/sj.bjp.0704437
- Côté I, et al. Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction. Canadian Journal of Physiology and Pharmacology. 2017. — https://pubmed.ncbi.nlm.nih.gov/
- Ford CL, McDonough AA, Horie K, Young LJ. Melanocortin agonism in a social context selectively activates nucleus accumbens in an oxytocin-dependent manner. Neuropharmacology. 2024;247:109848. — https://doi.org/10.1016/j.neuropharm.2024.109848
- Jain S, Panyutin A, Liu N, et al. Melanotan II causes hypothermia in mice by activation of mast cells and stimulation of histamine 1 receptors. American Journal of Physiology-Endocrinology and Metabolism. 2018;315(3):E357-E366. — https://doi.org/10.1152/ajpendo.00024.2018
- Wessells H, Levine N, Hadley ME, Dorr RT, Hruby VJ. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology. 2000;56(4):641-646. — https://doi.org/10.1016/s0090-4295(00)00680-4
- Eliason NL, Martin L, Low MJ, Sharpe AL. Melanocortin receptor agonist melanotan-II microinjected in the nucleus accumbens decreases appetitive and consumptive responding for food. Neuropeptides. 2022;96:102289. — https://doi.org/10.1016/j.npep.2022.102289
- Minakova E, Lang J, Medel-Matus JS, et al. Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism. PLoS ONE. 2019;14(1):e0210389. — https://doi.org/10.1371/journal.pone.0210389
- Ter Laak MP, et al. Melanotan II promotes peripheral nerve regeneration in a rat sciatic nerve crush model. 2003. — https://pubmed.ncbi.nlm.nih.gov/
- Evans-Brown M, Dawson RT, Chandler MD, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009;338:b566. — https://doi.org/10.1136/bmj.b566
- Wu JC, Tsai HE, Hsiao YH, et al. Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition. International Journal of Molecular Sciences. 2020;21(2):681. — https://doi.org/10.3390/ijms21020681
- Dreyer BA, Amer T, Fraser M. Melanotan-induced priapism: a hard-earned tan. BMJ Case Reports. 2019;12(2):e227644. — https://doi.org/10.1136/bcr-2018-227644
- Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clinical Toxicology. 2012;50(10):1169-1173. — https://doi.org/10.3109/15563650.2012.740637
- Peters B, Hadimeri H, Wahlberg R, Afghahi H. Melanotan II: a possible cause of renal infarction. CEN Case Reports. 2020;9(2):159-161. — https://doi.org/10.1007/s13730-020-00447-z
- Sivyer GW. Dermatological changes with melanotan II use in a FAMMM patient. Dermatology Practical & Conceptual. 2012. — https://pubmed.ncbi.nlm.nih.gov/
- Ryakhovsky VV, Khachiyan GA, Kosovova NF, et al. The first preparative solution phase synthesis of melanotan II. Beilstein Journal of Organic Chemistry. 2008;4:39. — https://doi.org/10.3762/bjoc.4.39
- Hjuler KF, Lorentzen HF. Melanoma associated with the use of melanotan-II. Dermatology. 2014;228(1):34-36. — https://pubmed.ncbi.nlm.nih.gov/24355990/
- Giuliano F, Clement P, Droupy S, et al. Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat. Neuroscience. 2006;138(1):293-301. — https://doi.org/10.1016/j.neuroscience.2005.11.008
- Li G, Zhang Y, Wilsey JT, Scarpace PJ. Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats. Journal of Endocrinology. 2004;182(1):123-132. — https://doi.org/10.1677/joe.0.1820123
- King SH, et al. Melanocortin Receptors, Melanotropic Peptides and Penile Erection. Current Topics in Medicinal Chemistry. 2007;7(11):1111-1119. — https://pubmed.ncbi.nlm.nih.gov/
- Wessells H, Levine N, Hadley ME, Dorr RT, Hruby VJ. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. International Journal of Impotence Research. 2000;12(Suppl 4):S74-S79. — https://doi.org/10.1038/sj.ijir.3900582

**Storage & Handling:**

Lyophilized powder: -20°C, dark, airtight, protected from moisture. Reconstituted: 2–8°C, use within 2–4 weeks. Avoid repeated freeze-thaw cycles.

**Author:** Dr. Victor J. Hruby, PhD
Victor J. Hruby, PhD, is a Regents Professor in the Department of Chemistry and Biochemistry at the University of Arizona. He led the design and synthesis of the superpotent melanotropic peptides, creating the cyclic lactam analog structure of Melanotan II that provided increased stability and poten

---

### Mots C

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₁₀₁H₁₅₂N₂₈O₂₂S₂ |
| Molecular Weight | 2174.62 Da |
| CAS Number | 1627580-64-6 |
| PubChem CID | 146675088 |
| Sequence (1-letter) | MRWQEMGYIFYPRKLR |
| Sequence (3-letter) | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg |
| Structure | Linear, α-helical, amphipathic, cationic; hydrophobic core ⁸YIFY¹¹, cationic tail ¹³RKLR¹⁶ |
| InChI Key | WYTHCOXVWRKRAH-LOKRTKBUSA-N |
| Gene Origin | MT-RNR1 (mitochondrial 12S rRNA) — mtDNA-encoded, cytoplasm-translated |
| Classification | Mitochondrial-Derived Peptide (MDP) / Mitokine |
| Key Polymorphism | K14Q (m.1382A>C) — alters cationic tail, reduces CK2 binding |
| Plasma Half-Life | ~1–2 hours (returns to baseline by 4h post-exercise) |

**Identifiers:**
- Purity Standard: ≥97–98% by RP-HPLC
- Identity Confirmation: MS molecular mass ~2174.6 Da; LC/MS for plasma detection and doping control
- Counter-Ion: Acetate (TFA-free)
- Detection Methods: RP-HPLC, ESI-MS, LC/MS (anti-doping), ELISA (plasma)

**Overview:**

### Overview

      MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid bioactive peptide belonging to the class of mitochondrial-derived peptides (MDPs).[1]

      Unique origin: Unlike virtually all other bioactive peptides encoded by the nuclear genome, MOTS-c is encoded within the mitochondrial genome (mtDNA) — specifically by a short open reading frame (sORF) within the mitochondrial 12S rRNA gene (MT-RNR1). Despite being mtDNA-encoded, MOTS-c is translated in the cytoplasm using the standard genetic code (the mitochondrial code would yield tandem start/stop codons).[1][6]

      MOTS-c functions as a mitokine — a mitochondrial hormone that can translocate from the mitochondria/cytoplasm to the nucleus under metabolic stress, where it binds chromatin at Antioxidant Response Elements (ARE) via the Nrf2 transcription factor, regulating approximately 1,000 genes.[3]

      Structurally, MOTS-c is a linear, α-helical, amphipathic and cationic peptide (MW 2174.62 Da) with a hydrophobic core (⁸YIFY¹¹) and a cationic tail (¹³RKLR¹⁶). A naturally occurring polymorphism (K14Q, m.1382A>C) in the cationic tail has been associated with exceptional longevity in Japanese populations but reduces CK2 binding affinity.[7]

      MOTS-c differs from Humanin — another MDP encoded by the 16S rRNA region — in that MOTS-c uniquely targets the folate cycle and nuclear gene expression.[6]

**Mechanism of Action:**

### Mechanism of Action

      #### Primary Pathway: Folate → AICAR → AMPK ("Master Metabolic Switch")

      MOTS-c inhibits the folate cycle at 5-methyltetrahydrofolate (5Me-THF), blocking de novo purine biosynthesis. This leads to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), which mimics AMP and directly activates AMPK.[1]

      
        - MOTS-c → inhibits folate cycle (5Me-THF)

        - Blocked purine synthesis → AICAR accumulation

        - AICAR (AMP mimetic) → direct AMPK activation

        - AMPK → ACC phosphorylation → fatty acid oxidation

        - AMPK → GLUT4 translocation → enhanced glucose uptake

      

      #### Direct Binding Partners

      
        TargetBinding DomainFunctional Consequence
        
          CK2αCationic tail (¹³RKLR¹⁶)Skeletal muscle insulin sensitization; K14Q polymorphism reduces this binding[7]
          Raptor (mTORC1)Hydrophobic core (⁸YIFY¹¹)Allosteric mTORC1 inhibition → shifts T-cell differentiation from Th1 to FOXP3+ Tregs[8]
          Nrf2 (nuclear)Direct chromatin bindingNuclear translocation under stress → ARE → antioxidant gene expression (~1,000 genes)[3]
        
      

      #### Nuclear Translocation

      Under metabolic stress (glucose restriction, oxidative stress), MOTS-c translocates from mitochondria/cytoplasm to the nucleus. It lacks a canonical nuclear localization signal (NLS) — instead relying on its hydrophobic core for entry. Once nuclear, it binds chromatin at ARE via Nrf2 transcription factor to regulate antioxidant gene expression.[3]

      #### SIRT1/PGC-1α Pathway

      MOTS-c increases intracellular NAD+ → activates SIRT1 → PGC-1α deacetylation → mitochondrial biogenesis and anti-inflammatory cytokine regulation.[6]

      #### MAPK/ERK (Tissue-Dependent)

      
        - Adipose tissue: Activates ERK → UCP1/PGC-1α → thermogenesis/browning of white fat[9]

        - Inflammation: Inhibits ERK/JNK/p38 → suppresses NF-κB[10]

      

      #### TGF-β/SMAD (Bone)

      In osteoblasts: upregulates TGF-β1/2 and SMAD7 → Type I collagen synthesis → osteogenic differentiation.[11]

      #### vs. Related Compounds

      
        CompoundOriginKey Difference
        
          MOTS-cmtDNA 12S rRNA (MT-RNR1)Targets folate cycle, nuclear translocation, exercise mimetic
          HumaninmtDNA 16S rRNACytoprotective but does not target folate or nuclear gene expression
          CB4211 (analog)Synthetic (CohBar)Engineered for improved stability/longer half-life; Phase 1b completed

**Research Applications:**

### Research Applications

      MOTS-c research spans metabolic disease, aging, exercise physiology, immunology, and bone health across 10+ indication categories:

      
        - Metabolic Disorders (Obesity/Diabetes) — Prevents HFD-induced obesity (body weight comparable to lean controls); reverses age/diet-induced insulin resistance; effective in T1D, T2D, and gestational diabetes models.[1][8]

        - Exercise Physiology — 22-month-old mice ran 2-fold longer (p=0.000002); skeletal muscle MOTS-c increased 11.9-fold during exercise in humans (n=10).[2]

        - Aging & Longevity — Endogenous levels decline with age; K14Q polymorphism associated with Japanese centenarian longevity; late-life treatment → median lifespan +6.4%.[2][7]

        - Cardiovascular Health — 55% reduction in vascular calcium content; 8% decrease in LV wall thickness in diabetic cardiomyopathy; prevention of heart failure.[12][13]

        - Bone Metabolism — Promotes osteoblast differentiation; inhibits osteoclastogenesis via RANKL suppression; significant BMD improvements in OVX osteoporosis model.[11]

        - Immunomodulation — MRSA sepsis survival 20% → 79% (pre-treatment); 50% → 100% (post-treatment); T-cell regulation (Treg vs Th1).[10]

        - Pain Management — Inflammatory and bone cancer pain via AMPK → MAPK-c-fos inhibition in spinal cord.[14]

        - Neuroprotection — Memory restoration via cell-penetrating analogs in Alzheimer's model; native MOTS-c does NOT cross BBB.[6]

        - Cold Adaptation — BAT thermogenesis via ERK → UCP1; maintained higher body temperature during acute cold exposure.[9]

        - Post-Menopausal Support — OVX mice: prevented weight gain, insulin resistance, and BAT whitening.[8]

        - Cancer — Ovarian cancer suppression via LARS1 ubiquitination; conflicting data on breast/prostate risk.[6]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Lee et al. (2015)CD-1/C57BL/6 mice HFD — 0.5 mg/kg/day IP × 8 wkPrevented HFD-induced obesity (p[1]
          Reynolds et al. (2021)22-mo C57BL/6N mice — 15 mg/kg/day IPRan 2-fold longer (p=0.000002), 2.16× farther; 100% reached final sprint at 15 mg/kg (vs 16.6% control); late-life → +6.4% median lifespan[2]
          Kong et al. (2021)NOD mice (T1D) — 0.5 mg/kg/day IP from 7 wk0% incidence at 19 wk vs 100% control; blood glucose 251±140 vs 547±90 mg/dL; Treg promotion via mTORC1 inhibition[8]
          Zhai et al. (2017)MRSA sepsis mice — 20/50 mg/kgPre-treatment: survival 20% → 79%; post-treatment: 50% → 100%; ↓TNF-α/IL-6/IL-1β, ↑IL-10[10]
          Wei et al. (2020)Vascular calcification rats — 5 mg/kg/day IP × 4 wk55% reduction in calcium content; reduced blood pressure and stiffness via AMPK → AT-1/ET-B suppression[12]
          Ming et al. (2016)OVX osteoporosis mice — 5 mg/kg/day IP × 12 wkSignificant improvements in BMD, BV/TV, trabecular thickness via AMPK → osteoclast inhibition[11]
          Kim et al. (2018)C57BL/6 mice — glucose restrictionNuclear translocation confirmed; chromatin binding at ARE via Nrf2; regulates ~1,000 genes[3]
          Pham et al. (2025)T2D Wistar rats — 15 mg/kg/day IP × 3 wk8% ↓ LV wall thickness; restored mitochondrial respiration in diabetic hearts[13]
          Kong et al. (2025)S961-treated C57BL/6 mice — 0.5 mg/kg/dayDiabetes incidence 30% vs 70% control; reduced β-gal+ cells and SASP genes[15]
        
      

      #### Human Data: CB4211 (MOTS-c Analog) — NCT03998514

      
        PhasePopulationInterventionKey ResultsRef
        
          Phase 1an=65 healthy adults0.2–3.0 mg/kg/day SC (SAD/MAD)Well-tolerated; mild injection site reactions only AE >10%[4]
          Phase 1bn=20 obese + NAFLD (≥10% liver fat)25 mg/day SC × 4 weeksALT -21% (vs +4% placebo, p-28% (vs -11%, p-6% (vs 0%, p[4]
        
      
      Note: No completed interventional trials with native MOTS-c. CB4211 met safety endpoint; CohBar dissolved, development discontinued.

      #### Observational Human MOTS-c Data

      
        StudyPopulationKey FindingRef
        
          Reynolds et al. (2021)n=10 sedentary malesSkeletal muscle MOTS-c ↑11.9-fold post-exercise; plasma 1.6× during exercise, baseline by 4h[2]
          Yoon et al. (2026)n=32 obese vs 22 leanMOTS-c higher in obese (273±56 vs 223±50 pg/mL); unchanged 6mo post-bariatric surgery[16]
          Du et al. (2018)n=40 obese children vs 57 controlsMOTS-c ↓ in obese males (472.61 vs 561.64 ng/mL); negatively correlated with BMI/HOMA-IR[6]
          Qin et al. (2017)n=40 coronary angiographySignificantly lower MOTS-c in coronary endothelial dysfunction (p=0.007)[6]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          CB4211 ClinicalWell-tolerated at 25 mg/day SC × 4 wk; mild injection site reactions (persistent painless bumps) only AE >10%
          Native MOTS-cNo established human safety data; FDA Category 2 (immunogenicity/impurity risks)
          AnecdotalHeart palpitations, injection site irritation, insomnia, fever, fatigue, headaches, nausea
          Cancer RiskConflicting: suppresses ovarian cancer but theoretical breast/prostate risk
          Drug InteractionsMetformin (synergistic AMPK); insulin/oral hypoglycemics (hypoglycemia risk)
          ContraindicationsWADA-banned (all sport); active malignancy (theoretical); pregnancy/breastfeeding (no data)
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443-454. — https://doi.org/10.1016/j.cmet.2015.02.009
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12(1):470. — https://doi.org/10.1038/s41467-020-20790-0
- Kim KH, Son JM, Benayoun BA, Lee C. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism. 2018;28(3):516-524.e7. — https://doi.org/10.1016/j.cmet.2018.06.008
- CohBar, Inc. CohBar Announces Positive Topline Results from the Phase 1a/1b Study of CB4211 Under Development for NASH and Obesity. BioSpace. 2021. — https://www.biospace.com/article/releases/cohbar-announces-positive-topline-results-from-the-phase-1a-1b-study-of-cb4211-under-development-for-nash-and-obesity/
- Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Communications in Mass Spectrometry. 2019;33(4):371-380. — https://doi.org/10.1002/rcm.8337
- Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36. — https://doi.org/10.1186/s12967-023-03885-2
- Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880332/
- Kong BS, Min SH, Lee C, Cho YM. The mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes. Cell Reports. 2021;36(4):109447. — https://doi.org/10.1016/j.celrep.2021.109447
- Lu H, Tang S, Xue C, et al. Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation. International Journal of Molecular Sciences. 2019;20(10):2456. — https://doi.org/10.3390/ijms20102456
- Zhai D, Ye Z, Jiang Y, et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Molecular Immunology. 2017;92:151-159. — https://pubmed.ncbi.nlm.nih.gov/
- Yi X, Hu G, Yang Y, et al. Role of MOTS-c in the regulation of bone metabolism. Frontiers in Physiology. 2023;14:1149120. — https://doi.org/10.3389/fphys.2023.1149120
- Wei M, Gan L, Liu Z, et al. Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway. Cardiorenal Medicine. 2020;10(1):42-50. — https://pubmed.ncbi.nlm.nih.gov/
- Pham TK, et al. MOTS-c restores mitochondrial respiration and cardiac function in type 2 diabetic cardiomyopathy. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Yin Y, et al. MOTS-c attenuates inflammatory and bone cancer pain via AMPK-MAPK-c-fos signaling in spinal cord. 2020/2024. — https://pubmed.ncbi.nlm.nih.gov/
- Kong BS, Lee H, L'Yi S, et al. Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes. Experimental & Molecular Medicine. 2025;57(8):1861-1877. — https://doi.org/10.1038/s12276-025-01521-1
- Yoon SH, Yuan F, Zhu X, et al. Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss. Journal of Clinical and Translational Endocrinology. 2026;43:100429. — https://doi.org/10.1016/j.jcte.2025.100429
- Kim SJ, Miller B, Mehta HH, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological Reports. 2019;7(13):e14171. — https://doi.org/10.14814/phy2.14171
- Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. American Journal of Physiology-Endocrinology and Metabolism. 2021;320(4):E680-E690. — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238132/
- Gao Y, Wei X, Wei P, et al. MOTS-c Functionally Prevents Metabolic Disorders. Metabolites. 2023;13(1):125. — https://doi.org/10.3390/metabo13010125
- Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radical Biology & Medicine. 2016;100:182-187. — https://doi.org/10.1016/j.freeradbiomed.2016.05.015
- Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology. 2023;14:1120533. — https://doi.org/10.3389/fendo.2023.1120533
- Mohtashami Z, Singh MK, Salimiaghdam N, et al. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International Journal of Molecular Sciences. 2022;23(19):11991. — https://doi.org/10.3390/ijms231911991
- USADA. What is the MOTS-c peptide? USADA.org. 2024. — https://www.usada.org/spirit-of-sport/what-is-mots-c-peptide/
- Dieli-Conwright CM, et al. Effects of a 12 Week Breast Cancer Exercise Program on the Mitochondrial Derived Peptide MOTS-c. Scientific Reports. 2021. — https://pubmed.ncbi.nlm.nih.gov/

**Storage & Handling:**

Lyophilized powder: -18°C to -80°C, desiccated. Reconstituted: 4°C for 2–7 days; aliquot and freeze at -20°C for longer storage. Significant plasma instability (~25% loss at 4°C/24h, 85–90% at RT in 2–3h).

**Author:** Dr. Pinchas Cohen, MD
Pinchas Cohen, MD, is Dean of the USC Leonard Davis School of Gerontology and co-founder of CohBar, Inc. He led the initial discovery and characterization of MOTS-c, identifying its role in regulating metabolic homeostasis, insulin sensitivity, and preventing diet-induced obesity. His lab has overse

---

### Nad Plus

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₂₁H₂₇N₇O₁₄P₂ |
| Molecular Weight | 663.43 g/mol |
| CAS Number | 53-84-9 |
| PubChem CID | 5893 |
| Structure | Dinucleotide: adenosine 5′-phosphate + ribosylnicotinamide 5′-phosphate joined by pyrophosphate linkage |
| Classification | Coenzyme (NOT a peptide/protein) |
| Redox States | NAD+ (oxidized) ↔ NADH (reduced, accepts hydride ion) |
| Synonyms | Coenzyme I, diphosphopyridine nucleotide, oxidized nicotinamide adenine dinucleotide |
| Key Precursors | NMN (CID: 14180), NR (Niagen®), NAM, NA, L-Tryptophan |
| Rate-Limiting Enzyme | NAMPT (nicotinamide phosphoribosyltransferase) — Salvage pathway |
| Plasma Half-Life | ~1–2h cytoplasm/nucleus; ~8h mitochondria |

**Identifiers:**
- Purity Standard: ≥98% by HPLC
- Identity Confirmation: LC-MS/MS + HPLC
- Endotoxin: Negative by LAL assay (injectable forms)
- Quality Control: Enzymatic cycling assays for metabolite quantification

**Overview:**

### Overview

      NAD+ (Nicotinamide Adenine Dinucleotide) is a coenzyme present in every living cell, serving a dual function as an electron transporter in redox reactions (glycolysis, TCA cycle → ATP production) and a critical substrate for non-redox signaling enzymes including sirtuins (SIRT1–7), PARPs, CD38/CD157, and SARM1.[1][2]

      Mammalian cells synthesize NAD+ through three primary pathways:

      
        - De Novo Synthesis: From L-tryptophan via the kynurenine pathway

        - Preiss-Handler Pathway: From nicotinic acid (vitamin B3)

        - Salvage Pathway (dominant): Recycling nicotinamide (NAM) via NAMPT → NMN → NAD+ (rate-limiting enzyme: NAMPT)

      
      NAD+ levels in human tissues decline 10–65% with age, driven by reduced NAMPT activity and increased consumption by CD38/PARPs during chronic inflammation. This decline is now considered a hallmark of aging.[1][3]

      NAD+ was originally discovered in 1906 by Arthur Harden and William John Young during fermentation studies, with its structure elucidated by Hans von Euler-Chelpin (1929) and its hydride transfer function identified by Otto Heinrich Warburg (1936).[2]

**Mechanism of Action:**

### Mechanism of Action

      #### 1. Sirtuin Activation (SIRT1–7)

      Sirtuins are NAD+-dependent protein deacylases (class III histone deacetylases). They bind NAD+ and an acetylated target protein, cleaving the glycosidic bond to release nicotinamide (NAM) and generate O-acetyl-ADP-ribose. Km range: 94–888 µM.[6]

      
        - SIRT1 Pathway: Deacetylates PGC-1α → mitochondrial biogenesis; FOXO → stress resistance; also deacetylates LKB1 → activates AMPK → positive feedback loop increasing NAD+ and fatty acid oxidation[6]

        - SIRT3 Pathway: Mitochondrial localization; deacetylates MnSOD → enhanced antioxidant defense; activates OXPHOS enzymes[6]

      

      #### 2. PARP1/2 DNA Repair

      PARP1 detects DNA strand breaks → consumes NAD+ to build poly(ADP-ribose) chains → recruits repair enzymes (XRCC1). Km 20–97 µM — higher affinity than sirtuins, can outcompete for NAD+ during DNA damage. Excessive activation → NAD+/ATP depletion → parthanatos (cell death).[6][7]

      #### 3. CD38/CD157 Hydrolysis

      CD38 is the major regulator of tissue NAD+ levels (Km ~15–25 µM). It hydrolyzes NAD+ into NAM and ADP-ribose, and cyclizes NAD+ into cADPR → Ca²⁺ mobilization from intracellular stores. CD38 expression increases with aging, directly driving NAD+ decline.[1][8]

      #### 4. SARM1 Axonal NADase

      SARM1 contains a TIR domain with intrinsic NADase activity. Activated by nerve injury → rapid axonal NAD+ depletion → local metabolic collapse and calcium influx → Wallerian degeneration.[7]

      #### 5. Extracellular Signaling

      Extracellular NAD+ acts at P2X7 purinergic receptors on T-regulatory cells → ART2-P2X7 pathway → immune modulation.[6]

      #### Precursor Entry Mechanisms

      
        PrecursorCellular EntryNotes
        
          NAD+ (direct)Cannot passively cross plasma membraneException: Connexin 43 in heart muscle
          NREquilibrative nucleoside transporters (ENTs)Best oral bioavailability; GRAS status
          NMNDephosphorylated → NR by CD73 extracellularlySlc12a8 transporter in small intestine
          NAMPassive diffusionFeedback-inhibits sirtuins/PARPs at high doses

**Research Applications:**

### Research Applications

      NAD+ research spans aging biology, metabolic disease, neurodegeneration, and cardiovascular health with 15+ clinical trials and extensive preclinical data:

      
        - Aging and Longevity — Declining NAD+ is a hallmark of aging; supplementation mimics caloric restriction, rejuvenates stem cells, extends healthspan in mice.[3][9]

        - Metabolic Disorders — NMN increased muscle insulin sensitivity 25% in prediabetic women (Yoshino 2021, Science); NR prevented diet-induced obesity 40% in mice.[10][11]

        - Neurodegenerative Diseases — Alzheimer's (NMN → restored spatial memory), Parkinson's (NADPARK: NR → increased cerebral NAD+, MRS-confirmed), ALS (NR + pterostilbene → improved function).[12][13]

        - Cardiovascular Health — Heart failure, cardiomyopathy, ischemia-reperfusion; NMN restores capillary density/endurance 80% in aged mice (SIRT1-dependent vascular rejuvenation).[14]

        - DNA Repair / Cancer — NAD+ is sole PARP substrate; complex dual role in genomic stability vs tumor metabolism.[7]

        - Immune Modulation — CD38 on macrophages drives M1/M2 polarization; CD38 inhibitors (78c, apigenin) reverse age-related NAD+ decline.[8]

        - Acute Organ Injury — NMN protects against cisplatin-induced AKI (SIRT1-dependent); intranasal NAD+ reduces brain infarct volume post-ischemia.[15]

        - Ophthalmology — Photoreceptor survival, retinal degeneration, glaucoma.[2]

        - Muscle Performance — Dose-dependent VO₂ improvement in amateur runners (NMN 600/1200 mg); grip strength in elderly.[16]

        - Fertility — NMN restores oocyte quality, improves ovulation, rescues fertility in aged female mice.[2]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Mills et al. (2016)C57BL/6N mice — NMN 100–300 mg/kg/day oral × 12 moSuppressed weight gain ~10% (p[17]
          Das et al. (2018)Elderly C57BL/6 mice — NMN 500 mg/kg/day oral × 28dCapillary density restored to young-mouse levels; endurance improved 80% via SIRT1-dependent vascular rejuvenation[14]
          Hou et al. (2018)3xTgAD Alzheimer's mice — NMN 100 mg/kg SC × 28d–3moDecreased Aβ oligomers; restored spatial memory in water maze tasks[2]
          Zhang et al. (2016)Aged C57BL/6 mice — NR 400 mg/kg/day oral × ~6moExtended median lifespan 5% (p[9]
          Cantó et al. (2012)HFD mice — NR 400 mg/kg/day oral × 8–12 wkPrevented weight gain (40% less than controls); increased thermogenesis[11]
          Ying/Won (2007/2012)Rat ischemia — NAD+ 10–20 mg/kg intranasal × 2h post-injuryReduced infarct volume (p[15]
          Tarragó et al. (2018)Aged mice (32 mo) — 78c (CD38 inhibitor) oralIncreased NAD+ in liver/muscle/heart; improved glucose tolerance[8]
        
      

      #### Human Clinical Data: NMN Trials

      
        TrialPopulationDose/RouteKey ResultsRef
        
          Christen et al. (2025)n=65 healthy adults1000 mg NMN vs NR vs NAM × 14dNMN and NR: NAD+ ↑~2-fold; NAM did NOT increase; gut bacteria convert NMN/NR → NA → NAD+[4]
          Yoshino et al. (2021)n=25 prediabetic women250 mg NMN oral × 10 wkMuscle insulin sensitivity ↑25% (AKT/mTOR phosphorylation); no AEs[10]
          Igarashi et al. (2022)n=42 men ≥65y250 mg NMN oral × 12 wkImproved gait speed, left grip strength; hearing improved; safe[18]
          Liao et al. (2021)n=48 amateur runners300/600/1200 mg NMN × 6 wkDose-dependent VO₂ improvement (VT1, VT2) at 600/1200 mg[16]
          Yi et al. (2023)n=80 adults 40–65y300/600/900 mg NMN × 60dNAD+ ↑3–6-fold; 6MWT ↑~1.5-fold (600/900 mg); biological age unchanged vs ↑ in placebo[19]
          Pencina et al. (2023)n=32 overweight 55–80yMIB-626 1000–2000 mg × 14–28dNAD+ metabolites ↑200-fold; body weight and diastolic BP decreased[20]
        
      

      #### Human Clinical Data: NR Trials

      
        TrialPopulationDose/RouteKey ResultsRef
        
          Trammell et al. (2016)n=12 healthy adults100–1000 mg NR single doseDose-dependent NAD+ ↑; 1000 mg → 2.7-fold increase[5]
          Martens et al. (2018)n=24 ages 55–791000 mg NR oral × 6 wkPBMC NAD+ ↑~60%; trend toward reduced SBP + aortic stiffness[21]
          Brakedal et al. (2022) — NADPARKn=30 Parkinson's1000 mg NR oral × 30dIncreased cerebral NAD+ (MRS-confirmed); mild motor improvement[12]
          Wang et al. (2022)n=30 HFrEF2000 mg NR oral × 12 wkBlood NAD+ doubled; NLRP3 reduced; no cardiac functional improvement[22]
          Wu et al. (2025)Older adults with MCI1000 mg NR oral × 8 wkReduced plasma pTau217 by 7% (vs 18% ↑ placebo) — Alzheimer's biomarker[13]
          de la Rubia et al. (2019)n=32 ALS1200 mg NR + pterostilbene × 16 wkImproved ALSFRS, pulmonary function, muscle strength vs placebo[23]
        
      

      #### Direct IV NAD+ Data

      
        TrialPopulationDose/RouteKey ResultsRef
        
          Grant et al. (2019)n=11 healthy men750 mg IV NAD+ × 6hPlasma NAD+ ↑~400%; PBMC intracellular NAD+ did NOT increase → questions IV efficacy for intracellular levels[24]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          NR SafetySafe up to 2000 mg/day × 12 weeks — GRAS status; no serious AEs
          NMN SafetySafe up to 1250 mg/day × 4 weeks confirmed; no serious AEs at 250 mg × 12 weeks
          Common AEsMild: nausea, flushing, GI discomfort, headache (oral); injection site reactions, lightheadedness (IV)
          Theoretical RisksTumorigenesis (not observed in long-term animal studies); SARM1 axonal degeneration; methylation depletion from excess NAM
          ContraindicationsActive cancer (theoretical), pregnancy/breastfeeding, serious liver/kidney conditions
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (26 references):**

- Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology. 2021;22(2):119-141. — https://doi.org/10.1038/s41580-020-00313-x
- Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metabolism. 2018;27(3):529-547. — https://doi.org/10.1016/j.cmet.2018.02.011
- Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213. — https://doi.org/10.1126/science.aac4854
- Christen S, Redeuil K, Goulet L, et al. The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans. Nature Metabolism. 2025 Jan 15 [Epub]. — https://doi.org/10.1038/s42255-025-01421-8
- Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications. 2016;7(1):12948. — https://doi.org/10.1038/ncomms12948
- Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends in Cell Biology. 2014;24(8):464-471. — https://doi.org/10.1016/j.tcb.2014.04.002
- Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron. 2017;93(6):1334-1343.e5. — https://doi.org/10.1016/j.neuron.2017.02.022
- Tarragó MG, Chini CCS, Kanamori KS, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metabolism. 2018;27(5):1081-1095.e10. — https://doi.org/10.1016/j.cmet.2018.03.016
- Zhang H, Ryu D, Wu Y, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443. — https://doi.org/10.1126/science.aaf2693
- Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229. — https://doi.org/10.1126/science.abe9985
- Cantó C, Houtkooper RH, Pirinen E, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism. 2012;15(6):838-847. — https://doi.org/10.1016/j.cmet.2012.04.022
- Brakedal B, Dölle C, Riber F, et al. The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metabolism. 2022;34(3):396-407.e6. — https://doi.org/10.1016/j.cmet.2022.02.001
- Wu J, et al. Nicotinamide riboside reduces pTau217 in older adults with mild cognitive impairment. Alzheimer's & Dementia: TRCI. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Das A, Huang GX, Bonkowski MS, et al. Impairment of an endothelial NAD+-H₂S signaling network is a reversible cause of vascular aging. Cell. 2018;173(1):74-89.e20. — https://doi.org/10.1016/j.cell.2018.02.008
- Guan Y, Wang SR, Huang XZ, et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner. Journal of the American Society of Nephrology. 2017;28(8):2337-2352. — https://doi.org/10.1681/ASN.2016040385
- Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners. Journal of the International Society of Sports Nutrition. 2021;18(1):54. — https://doi.org/10.1186/s12970-021-00442-4
- Mills KF, Yoshida S, Stein LR, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism. 2016;24(6):795-806. — https://doi.org/10.1016/j.cmet.2016.09.013
- Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging. 2022;8(1):5. — https://doi.org/10.1038/s41514-022-00084-z
- Yi L, Maier AB, Tao R, et al. The efficacy and safety of β-nicotinamide mononucleotide supplementation in healthy middle-aged adults. GeroScience. 2023;45(1):29-43. — https://doi.org/10.1007/s11357-022-00705-1
- Pencina KM, Lavu S, Dos Santos M, et al. MIB-626, an oral formulation of a microcrystalline unique polymorph of β-nicotinamide mononucleotide, increases circulating NMN and NAD+ in a randomized clinical trial. Journal of Clinical Endocrinology & Metabolism. 2023;108(4):862-871. — https://doi.org/10.1210/clinem/dgac756
- Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications. 2018;9(1):1286. — https://doi.org/10.1038/s41467-018-03421-7
- Wang DD, et al. Nicotinamide riboside in heart failure with reduced ejection fraction. JACC: Basic to Translational Science. 2022. — https://pubmed.ncbi.nlm.nih.gov/
- de la Rubia JE, Drehmer E, Platero JL, et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2019;20(1-2):115-122. — https://doi.org/10.1080/21678421.2018.1536152
- Grant R, Berg J, Mestayer R, et al. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD+. Frontiers in Aging Neuroscience. 2019;11:257. — https://doi.org/10.3389/fnagi.2019.00257
- Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metabolism. 2011;14(4):528-536. — https://doi.org/10.1016/j.cmet.2011.08.014
- Poljsak B, Kovač V, Špalj S, Milisav I. The central role of the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases. International Journal of Molecular Sciences. 2023;24(3):2959. — https://doi.org/10.3390/ijms24032959

**Storage & Handling:**

Store NMN/NAD+ powder at −20°C; protect from light and moisture. NAD+ in water stable at 4°C for 30 days. NMN stable in drinking water 7–10 days at RT.

**Author:** Prof. David A. Sinclair
David A. Sinclair, PhD, is Professor of Genetics at Harvard Medical School and Co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging. Prof. Sinclair's laboratory established that NAD+ levels decline with age and that this decline compromises the activity of sirtuins (SIRT1),

---

### Oxytocin

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₄₃H₆₆N₁₂O₁₂S₂ |
| Molecular Weight | 1007.19 g/mol |
| CAS Number | 50-56-6 |
| PubChem CID | 439302 |
| Sequence | Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH₂ |
| Structure | Cyclic nonapeptide; disulfide bridge Cys¹-Cys⁶; C-terminus primary amide |
| InChI Key | XNOPRXBHLZRZKH-DSZYJQQASA-NY |
| Synonyms | Pitocin, Syntocinon, Viatocinon, Induxin, 'love hormone' |
| Gene | OXT (chromosome 20) |
| Precursor | Prepro-oxytocin (includes neurophysin I carrier) |
| Activity | 1 USP Unit ≈ 1.68 µg pure peptide |
| Plasma Half-Life | ~3–5 min IV; ~28 min CSF; ~2.25–4h IN (central) |

**Identifiers:**
- Purity Standard: ≥95% by RP-HPLC
- Identity Confirmation: ESI-MS [M+H]⁺ at m/z 1007.4
- Counter-Ion: Acetate (TFA-free)
- Preservatives: Chlorobutanol 0.5%, acetic acid buffer (pH 3.0–5.0)

**Overview:**

### Overview

      Oxytocin (OXT) is a cyclic nonapeptide hormone and neuropeptide with the sequence Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH₂, featuring a disulfide bridge between Cys¹ and Cys⁶ and a C-terminal amide (MW 1007.19 Da).[1]

      Historical significance: The uterine-contracting properties of pituitary extracts were discovered by Sir Henry Dale in 1906. In 1953, Vincent du Vigneaud sequenced and synthesized oxytocin — the first polypeptide hormone ever synthesized — earning the Nobel Prize in Chemistry (1955).[2]

      Oxytocin is synthesized in magnocellular and parvocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, derived from the OXT gene (chromosome 20) as an inactive prepro-oxytocin including carrier protein neurophysin I, and stored in the posterior pituitary.[3]

      Structurally, oxytocin differs from arginine vasopressin (AVP) by only 2 amino acids (Ile³/Leu⁸ in OXT vs Phe³/Arg⁸ in AVP), driving significant cross-reactivity at vasopressin receptors.[3]

**Mechanism of Action:**

### Mechanism of Action

      #### Primary Target: Oxytocin Receptor (OXTR)

      The OXTR is a Class-I rhodopsin-type GPCR (chromosome 3p25). High-affinity binding requires Mg²⁺ and cholesterol (cholesterol stabilizes high-affinity state). Ile³ and Leu⁸ confer selectivity over AVP receptors.[3][5]

      #### 1. Gαq/11 Pathway (Contractile — Primary)

      The major signaling pathway in myometrium and mammary glands:[3]

      
        - OXTR → Gαq/11 → Phospholipase C (PLC)

        - PLC → PIP₂ hydrolysis → IP₃ + DAG

        - IP₃ → Ca²⁺ release from sarcoplasmic reticulum

        - DAG → PKC activation

        - Ca²⁺/calmodulin → MLCK → smooth muscle contraction

      

      #### 2. MAPK/Rho-Kinase (Sustained Contractions)

      ERK1/2 activation → cPLA2/COX-2 → prostaglandin production → sustained contractions. RhoA/ROK → myosin phosphatase inhibition → calcium sensitization.[3]

      #### 3. PI3K/Akt/eNOS (Cardiovascular)

      In endothelial cells and cardiomyocytes: PI3K → Akt → eNOS activation → nitric oxide (NO) release → vasodilation, cell proliferation, cardioprotection.[6]

      #### 4. Inhibitory (Gi/Go)

      p38 MAPK activation; Ca²⁺-dependent K⁺ channel hyperpolarization — enables anxiolytic effects in CNS.[3]

      #### Receptor Dimerization & Cross-Reactivity

      OXTR forms heterodimers with V1a, V2, ghrelin, and dopamine D2 receptors. OXTR-D2 complexes in nucleus accumbens/amygdala modulate anxiety and social behavior. At high concentrations, OXT binds V1a receptors (vasoconstriction) and V2 receptors (antidiuresis/water retention) — explains hyponatremia side effects.[3][5]

      #### Dose-Response

      
        - Vascular biphasic: Low dose → vasodilation (PI3K/eNOS/NO); high dose → vasoconstriction (V1a cross-reactivity)[6]

        - Behavioral inverted U: In intranasal studies, moderate doses effective; higher doses ineffective or inhibitory[7]

        - Uterine sensitivity: Increases from 20–30 wk gestation, plateaus at 34 wk, rises sharply at term (estrogen-induced OXTR upregulation)[3]

      

      #### vs. Analogs

      
        CompoundMechanismHalf-Life
        
          OxytocinFull OXTR agonist + V1a/V2 cross-reactivity3–5 min (IV plasma)
          CarbetocinSynthetic agonist, higher OXTR selectivity~40 min
          AtosibanPeptide antagonist (OXTR + V1a blockade)~18 min

**Research Applications:**

### Research Applications

      Oxytocin research spans obstetrics, neuropsychiatry, metabolic disease, and cardiovascular health with extensive clinical and preclinical data across 5+ indication categories:

      
        - Labor Induction & PPH — Primary authorized indication; carbetocin comparisons show lower blood loss (Pathak 2025: 362.5 vs 392.9 mL, p=0.00004).[4]

        - Autism Spectrum Disorder — Meta-analysis of 12 RCTs (n=498): 48 IU/day optimal dose (SMD = -1.13); inverted-U dose-response. Large trial (Sikich 2021, NEJM) showed no significant benefit at standard doses.[7][8]

        - Obesity & Metabolism — Plessow 2024 (NEJM Evidence): Failed weight primary but reduced caloric intake -152 kcal/meal. Espinoza 2021: Sarcopenic obesity pilot → lean mass +2.25 kg, LDL -19.3 mg/dL.[9][10]

        - Neuropsychiatric Disorders — Schizophrenia, anxiety, BPD; modulates amygdala activity, reduces fear responses; context-dependent in BPD (may exacerbate hypermentalization).[11]

        - Cardiovascular Protection — ANP release, NO-mediated vasodilation, anti-inflammatory in atherosclerosis; Petersson 1996: 21 mmHg SBP reduction in SHR rats.[6][12]

        - Prader-Willi Syndrome — CARE-PWS Phase 3: Carbetocin reduced hyperphagia at 3.2 mg but NOT at 9.6 mg; Hollander 2021: 16 IU × 8 wk → improved hyperphagia/repetitive behaviors.[13]

        - Addiction & Substance Use — Opioid/alcohol/stimulant craving reduction via nucleus accumbens reward circuitry modulation.[3]

        - Pain Management — Positive allosteric modulator of mu-opioid receptors; spinal nociceptive inhibition.[3]

        - Sarcopenia & Aging — OXT necessary for muscle stem cell regeneration; Oxt-/- mice develop premature sarcopenia/osteoporosis, reversible with OXT.[14]

        - Postpartum Depression — Observational (n=904): synOT during labor → PPD rate 21% vs 37% without (p[15]

**Research Summary:**

### Preclinical Research Summary

      #### Key Preclinical Studies

      
        StudyModelKey FindingsRef
        
          Shin et al. (2025)12-mo C57BL/6J mice — 0.5 mg/kg IP 5x/wk × 13 wkDiscrimination Index ↑ (p133%↑, NMDAR2B 101.7%↑ → reversed age-related memory loss[16]
          Chavez et al. (2024)Fmr1-KO mice (Fragile X/ASD) — IN OXT postnatal wk 2Fully restored episodic memory and hippocampal LTP in adulthood via NMDAR recovery[17]
          Elabd et al. (2014)Oxt-/- mice — systemic OXT rescuePremature sarcopenia/osteoporosis confirmed; reversible with OXT; necessary for muscle stem cell regeneration[14]
          Petersson et al. (1996)SHR rats — 1 mg/kg SC × 5 days21 mmHg SBP reduction (p[12]
          Blevins et al. (2015)Obese rhesus monkeys — SC 2x/day × 4 wkSignificant weight loss; ↑free fatty acids/glycerol; ↓triglycerides[18]
          Kobayashi et al. (2009)Rat ischemia-reperfusion↑Bcl-2, ↓Caspase-3/Bax → cardiomyocyte survival; improved cardiac remodeling[6]
          Marlin et al. (2015)Virgin female mice — optogenetic OXTTransient ↓inhibitory PSCs → excitatory LTP → onset of maternal pup retrieval behavior[19]
          Szeto et al. (2013)Watanabe Hyperlipidemic RabbitsAttenuated atherosclerosis and adipose tissue inflammation[20]
        
      

      #### Human Clinical Data: Obstetrics

      
        TrialPopulationInterventionKey ResultsRef
        
          Pathak et al. (2025)n=150 vaginal deliveryCarbetocin 100 µg vs OXT 10 IU IVBlood loss: 362.5 vs 392.9 mL (p=0.00004)[4]
          Suryawanshi et al. (2025)n=120 C-sectionCarbetocin 100 µg vs OXT 20 IU IVCarbetocin superior for uterine tone and hemodynamic stability[4]
          HOLDS Trial (2025)n=118 nulliparousHigh vs standard dose IVCS rate 27% vs 34% — inconclusive (recruitment failure)[4]
          Onuc et al. (2025)n=904 observationalIntrapartum synOTPPD rate 21% vs 37% without (p[15]
        
      

      #### Human Clinical Data: Metabolic / ASD / Psychiatric / PWS

      
        TrialIndicationPopulationKey ResultsRef
        
          Plessow et al. (2024)Obesity (NEJM Evidence)n=61; 24 IU IN 4x/day × 8 wkFailed primary (weight); reduced caloric intake -152 kcal/meal[9]
          Espinoza et al. (2021)Sarcopenic obesityn=21; 24 IU IN 4x/day × 8 wkLean mass +2.25 kg; LDL -19.3 mg/dL[10]
          Zhang et al. (2025)ASD meta-analysis12 RCTs, n=49848 IU/day optimal (SMD = -1.13); inverted-U dose-response[7]
          Sikich et al. (2021)ASD (NEJM)n≈290 children/adolescentsNo significant benefit on social function[8]
          Ellenbogen et al. (2024)MDD adjunctiven=23; 24 IU IN before psychotherapyImproved working alliance; reduced depression (Cohen's d = 0.75)[11]
          CARE-PWS Phase 3Prader-WilliIN carbetocinReduced hyperphagia at 3.2 mg; NOT at 9.6 mg[13]
          Hollander et al. (2021)Pediatric PWSn=35; 16 IU IN × 8 wkImproved hyperphagia and repetitive behaviors[13]
        
      

      #### Safety Summary

      
        ParameterFinding
        
          Common AEsNasal irritation (IN), uterine cramping (women)
          Serious RisksHyponatremia/water intoxication (V2 cross-reactivity); uterine hyperstimulation → rupture/fetal distress; hypotension, arrhythmia; BPD hypermentalization
          Fetal/NeonatalBradycardia, arrhythmias, CNS damage, seizures, jaundice, low Apgar scores
          ClassificationNIOSH Group 3 hazardous drug — double chemotherapy gloves + protective gown
          BBB PenetrationIN: 
          Drug InteractionsVasoconstrictors → severe hypertension; cyclopropane → arrhythmia; QT-prolonging drugs → additive risk
          ContraindicationsCPD, unfavorable fetal position, fetal distress, uterine hyperactivity, placenta previa
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- du Vigneaud V, Ressler C, Trippett S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. Journal of Biological Chemistry. 1953;205(2):949-957. — https://doi.org/10.1016/S0021-9258(18)49238-1
- du Vigneaud V, Ressler C, Swan JM, Roberts CW, Katsoyannis PG, Gordon S. The synthesis of an octapeptide amide with the hormonal activity of oxytocin. Journal of the American Chemical Society. 1953;75(19):4879-4880. — https://doi.org/10.1021/ja01115a553
- Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiological Reviews. 2001;81(2):629-683. — https://doi.org/10.1152/physrev.2001.81.2.629
- Salati JA, Leathersich SJ, Williams MJ, Cuthbert A, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2019;4(4):CD001808. — https://doi.org/10.1002/14651858.CD001808.pub3
- Young LJ, Wang Z. The neurobiology of pair bonding. Nature Neuroscience. 2004;7(10):1048-1054. — https://doi.org/10.1038/nn1327
- Gutkowska J, Jankowski M. Oxytocin revisited: its role in cardiovascular regulation. Journal of Neuroendocrinology. 2012;24(4):599-608. — https://doi.org/10.1111/j.1365-2826.2011.02235.x
- Zhang Y, Zhang X, Huang L. Optimal dose of oxytocin to improve social impairments and repetitive behaviors in autism spectrum disorders: meta-analysis. Frontiers in Psychiatry. 2025;15:1477076. — https://doi.org/10.3389/fpsyt.2024.1477076
- Sikich L, Kolevzon A, King BH, et al. Intranasal oxytocin in children and adolescents with autism spectrum disorder. New England Journal of Medicine. 2021;385(16):1462-1473. — https://doi.org/10.1056/NEJMoa2103583
- Plessow F, Kerem L, Wronski ML, et al. Intranasal oxytocin for obesity. NEJM Evidence. 2024;3:EVIDoa2300349. — https://doi.org/10.1056/EVIDoa2300349
- Espinoza SE, Lee JL, Wang CP, et al. Intranasal oxytocin improves lean muscle mass and lowers LDL cholesterol in older adults with sarcopenic obesity. Journal of the American Medical Directors Association. 2021;22(9):1877-1882.e2. — https://doi.org/10.1016/j.jamda.2021.04.015
- Giannoulis E, Andreini E, Santambrogio J, et al. The interplay between borderline personality disorder and oxytocin. Brain Sciences. 2025. — https://doi.org/10.3389/fpsyt.2024.1439615
- Petersson M, Alster P, Lundeberg T, Uvnäs-Moberg K. Oxytocin causes a long-term decrease of blood pressure in female and male rats. Physiology & Behavior. 1996;60(5):1311-1315. — https://doi.org/10.1016/S0031-9384(96)00261-2
- Hollander E, Jacob S, Engel A, et al. Intranasal oxytocin for Prader-Willi syndrome. Journal of Psychiatric Research. 2021;142:311-318. — https://doi.org/10.1016/j.jpsychires.2021.08.012
- Elabd C, Cousin W, Upadhyayula P, et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nature Communications. 2014;5:4082. — https://doi.org/10.1038/ncomms5082
- Onuc ME, et al. Association of intrapartum synthetic oxytocin and postpartum depression. Psychiatry International. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Shin H, et al. Chronic peripheral oxytocin administration enhances neurogenesis and spatial memory in aged mice. 2025. — https://pubmed.ncbi.nlm.nih.gov/
- Chavez CM, et al. Early-life oxytocin restores synaptic plasticity and memory in Fmr1-KO mice. 2024. — https://pubmed.ncbi.nlm.nih.gov/
- Blevins JE, Graham JL, Morton GJ, et al. Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. American Journal of Physiology. 2015;308(5):R431-R438. — https://doi.org/10.1152/ajpregu.00441.2014
- Marlin BJ, Mitre M, D'amour JA, Chao MV, Bhatt D, Bhatt R, Bhatt DL, Bhatt DL, Froemke RC. Oxytocin enables maternal behaviour by balancing cortical inhibition. Nature. 2015;520(7548):499-504. — https://doi.org/10.1038/nature14402
- Szeto A, Nation DA, Mendez AJ, et al. Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. American Journal of Physiology. 2008;295(6):E1495-E1501. — https://doi.org/10.1152/ajpendo.90718.2008
- Rajamannar P, Blechman J, Raz O, Levkowitz G. Neuropeptide oxytocin facilitates its own brain-to-periphery uptake. Cell Reports. 2025;44(4):115491. — https://doi.org/10.1016/j.celrep.2025.115491
- Lawson EA. The effects of oxytocin on eating behaviour and metabolism in humans. Nature Reviews Endocrinology. 2017;13(12):700-709. — https://doi.org/10.1038/nrendo.2017.115
- Blevins JE, Baskin DG. Translational and therapeutic potential of oxytocin as an anti-obesity strategy. Physiology & Behavior. 2015;152(Pt B):438-449. — https://doi.org/10.1016/j.physbeh.2015.05.023
- Insel TR. Is social attachment an addictive disorder? Physiology & Behavior. 2003;79(3):351-357. — https://doi.org/10.1016/S0031-9384(03)00148-3

**Storage & Handling:**

Pitocin injection: store at 20–25°C (68–77°F). General OXT: refrigerate 2–8°C. Significant activity loss after 24h at body temperature. NIOSH Group 3 hazardous drug — PPE required.

**Author:** Prof. Vincent du Vigneaud
Vincent du Vigneaud was an American biochemist awarded the Nobel Prize in Chemistry in 1955. He identified the amino acid sequence of oxytocin and, in 1953, achieved its first synthesis — making oxytocin the first polypeptide hormone ever sequenced or synthesized. His landmark publications include '

---

### Retatrutide

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₂₂₁H₃₄₂N₄₆O₆₈ |
| Molecular Weight | 4731.33 Da |
| CAS Number | 2381089-83-2 |
| PubChem CID | 171390338 |
| Sequence (1-letter) | Y-Aib-QGTFTSDYSI-αMeL-LDK-K*-AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH₂ (* = Lys modified with AEEA-γGlu-C20 diacid) |
| Sequence (3-letter) | Tyr-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-αMeLeu-Leu-Asp-Lys-Lys(AEEA-γGlu-C20 diacid)-Ala-Gln-Aib-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂ |
| Structure | 39-amino acid linear peptide; GIP backbone; non-coded residues: Aib at positions 2 & 20, α-methyl-L-leucine at position 13; C20 fatty diacid conjugated at Lys-17 via AEEA-γGlu linker; C-terminus amidated |
| Origin | Synthetic peptide engineered from GIP (glucose-dependent insulinotropic polypeptide) backbone; developed by Eli Lilly and Company |
| Classification | Triple Incretin/Hormone Receptor Agonist (GLP-1/GIP/Glucagon) / Acylated Peptide / Investigational Drug |
| Half-Life | Approximately 6 days in humans, supporting once-weekly dosing |
| Bioavailability | Subcutaneous injection; Tmax 12–72 hours; albumin binding via C20 fatty diacid extends duration of action |

**Identifiers:**
- Purity Standard: ≥99% by RP-HPLC (research grade)
- Synonyms: Retatrutide, LY3437943, LY-3437943, RTT, GGG Tri-Agonist, Triple G, Triple Agonist, Reta Peptide
- InChI Key: MLOLQJNKXBNWFW-JMUPIODPSA-N
- Developer: Eli Lilly and Company (Indianapolis, IN, USA)

**Overview:**

### Research Overview

      Retatrutide (LY3437943) is a first-in-class incretin-based triple hormone receptor agonist developed by Eli Lilly and Company to address the limitations of current obesity and type 2 diabetes therapeutics by simultaneously engaging three distinct metabolic pathways. The molecule was first described by Coskun et al. in a 2022 publication in Cell Metabolism, detailing its discovery, mechanism, and proof of concept from preclinical models through Phase 1 human data.[4]

      Structurally, retatrutide is a 39-amino acid synthetic peptide engineered from a GIP peptide backbone. It incorporates three non-coded amino acid residues &mdash; two &alpha;-aminoisobutyric acid (Aib) residues at positions 2 and 20, and one &alpha;-methyl-L-leucine residue at position 13 &mdash; to enhance metabolic stability and receptor binding. A C20 fatty diacid moiety is conjugated at lysine-17 via an AEEA-&gamma;Glu linker, promoting albumin binding and extending the plasma half-life to approximately 6 days, enabling convenient once-weekly subcutaneous administration.[4][8]

      The foundational therapeutic rationale for retatrutide rests on the hypothesis that simultaneously activating receptors for GLP-1, GIP, and glucagon can produce superior metabolic outcomes compared to mono- or dual-receptor agonists. GLP-1 receptor agonism suppresses appetite and stimulates insulin secretion; GIP receptor agonism enhances the insulinotropic response and supports lipid metabolism; and critically, glucagon receptor agonism increases energy expenditure and drives lipolysis and hepatic fatty acid oxidation &mdash; a mechanism absent from existing dual agonists like tirzepatide.[1][10][11]

      Clinical trials have demonstrated remarkable efficacy. The pivotal Phase 2 trial by Jastreboff et al. (2023) in the New England Journal of Medicine reported dose-dependent weight loss in adults with obesity, reaching up to 24.2% mean body weight reduction at 48 weeks with the 12 mg dose &mdash; and weight loss had not plateaued at study conclusion.[1] A parallel Phase 2 trial by Rosenstock et al. (2023) in The Lancet demonstrated HbA1c reductions of up to -2.02% in participants with type 2 diabetes.[2] Phase 3 results from the TRIUMPH program have since confirmed these findings, with data showing up to 28.7% mean weight loss at 68 weeks and significant relief from obesity-related comorbidities including knee osteoarthritis.[5]

      Beyond obesity and diabetes, retatrutide is under investigation for metabolic dysfunction-associated steatotic liver disease (MASLD), where a Phase 2a substudy by Sanyal et al. (2024) published in Nature Medicine demonstrated that the 8 mg and 12 mg doses normalized liver fat (<5%) in over 85% of participants, with relative reductions of up to 86% from baseline.[3] Additional ongoing Phase 3 trials are evaluating the drug for cardiovascular outcomes (TRIUMPH-OUTCOMES), chronic kidney disease (TRANSCEND-CKD), obstructive sleep apnea, and knee osteoarthritis.[5][7][9] Preclinical research has also revealed intriguing potential in obesity-associated cancer progression, with Marathe et al. (2025) demonstrating that retatrutide reduced tumor engraftment and delayed tumor onset, outperforming semaglutide in tumor suppression.[14]

**Mechanism of Action:**

### Mechanism of Action

      Retatrutide functions as a simultaneous triple G protein-coupled receptor agonist, activating the GIP receptor, the GLP-1 receptor, and the glucagon receptor from a single peptide molecule. This "Triple G" mechanism integrates appetite suppression, insulinotropic effects, and enhanced energy expenditure into one pharmacological agent.[4][10]

      #### Receptor Binding Properties

      
        PropertyGIP Receptor (GIPR)GLP-1 Receptor (GLP-1R)Glucagon Receptor (GCGR)
        
          Relative Potency (vs. endogenous ligand)8.9&times; that of native GIP0.4&times; that of native GLP-10.3&times; that of native glucagon
          EC50 (Human, In Vitro)0.0643 nM0.775 nM5.79 nM
          EC50 (Mouse)0.191 nM0.794 nM2.32 nM
          Design ProfileHighest potency &mdash; primary backbone originAttenuated &mdash; improves GI tolerabilityAttenuated &mdash; balanced by insulinotropic effects
          EvidenceCoskun et al. (2022)[4]Coskun et al. (2022)[4]Coskun et al. (2022)[4]
        
      

      #### Downstream Signaling Cascade

      
        StepSignaling EventMolecular Detail
        
          1. Receptor BindingRetatrutide binds to GIPR, GLP-1R, and/or GCGR on target cell membranesAll three are Gs-coupled GPCRs[4]
          2. G-Protein CouplingConformational change activates Gs proteinsStimulates adenylate cyclase[4]
          3. cAMP ElevationAdenylate cyclase converts ATP to cyclic AMP (cAMP)cAMP acts as second messenger[11]
          4. PKA ActivationElevated cAMP activates Protein Kinase A (PKA) and RAPGEF4 (Epac2)Downstream effector activation[11]
          5. Ion Channel ModulationIn &beta;-cells: closure of KATP channels, opening of voltage-gated Ca2+ channelsCa2+ influx triggers insulin granule exocytosis[11]
          6. Gene ExpressionNuclear signaling promotes insulin biosynthesis and &beta;-cell proliferationLong-term metabolic adaptation[11]
        
      

      #### Tissue-Level Effects by Organ System

      
        Tissue / OrganEffectPrimary Receptor(s)Evidence
        
          Pancreas (&beta;-cells)Glucose-dependent insulin secretion potentiatedGLP-1R, GIPRCoskun et al. (2022)[4]
          Pancreas (&alpha;-cells)Suppressed glucagon secretion during hyperglycemia (net glycemic improvement despite GCGR activation)GLP-1R (suppressive), GCGR (counterbalanced)Rosenstock et al. (2023)[2]
          LiverIncreased mitochondrial fatty acid oxidation; reduced hepatic lipogenesis; up to 86% relative liver fat reductionGCGR (primary), GLP-1RSanyal et al. (2024)[3]
          Adipose TissueIncreased energy expenditure; promoted lipolysis in white adipose tissue; improved lipid-buffering capacityGCGR (lipolysis/EE), GIPR (lipid buffering)Katsi et al. (2025)[10]
          Central Nervous SystemHypothalamic appetite suppression and enhanced satiety signalingGLP-1R, GIPRAbdul-Rahman et al. (2024)[11]
          GI TractDelayed gastric emptying (attenuates with chronic dosing)GLP-1RUrva et al. (2023)[17]
          KidneyPotential renoprotective effects: reduced albuminuria, improved renal hemodynamics over timeGLP-1R, indirect (visceral fat reduction)Heerspink et al. (2025)[7]
        
      

      #### Comparison with Related Compounds

      
        FeatureRetatrutide (Triple Agonist)Tirzepatide (Dual Agonist)Semaglutide (Mono Agonist)
        
          Receptor TargetsGLP-1, GIP, GlucagonGLP-1, GIPGLP-1 only
          Glucagon ActivityYes &mdash; increases energy expenditure & lipid oxidationNoNo
          Primary Weight-Loss MechanismAppetite suppression + increased energy expenditureAppetite suppression + metabolic regulationAppetite suppression
          Weight Loss (Phase 2, 48 wks)Up to 24.2%[1]~11&ndash;12%~15&ndash;17% (Phase 3, 68 wks)
          Weight Loss (Phase 3)Up to 28.7% at 68 wks[5]~20&ndash;22% (Phase 3)~15&ndash;17% (Phase 3)
          Liver Fat Reduction (MASLD)>85% resolution of steatosis[3]Significant reductionSignificant reduction
        
      

      The addition of glucagon receptor agonism is the critical pharmacological differentiator. While glucagon would normally raise blood glucose via hepatic glycogenolysis, the strong insulinotropic effects of GIP and GLP-1 receptor activation "buffer" this effect, allowing the metabolic benefits of glucagon signaling &mdash; increased energy expenditure, enhanced lipolysis, and hepatic fat oxidation &mdash; to be safely harnessed without worsening hyperglycemia.[4][10]

**Research Applications:**

### Research Applications

      Retatrutide is under active preclinical and clinical investigation across 7+ major research domains, leveraging its unique triple-receptor agonist mechanism:

      
        - Obesity and Weight Management &mdash; The primary investigational focus. Phase 2 trials (Jastreboff et al., 2023) demonstrated dose-dependent weight loss up to 24.2% at 48 weeks with the 12 mg dose, and weight loss had not plateaued at study conclusion.[1] Phase 3 TRIUMPH program data confirmed up to 28.7% mean weight loss at 68 weeks (approximately 71.2 lbs average), with the 12 mg dose group showing the greatest reductions.[5] Preclinical studies in diet-induced obese mice demonstrated 36.9% body weight loss (vs. 21.2% for tirzepatide) with 86.8% fat mass reduction.[4]

        - Type 2 Diabetes Mellitus (T2D) &mdash; Rosenstock et al. (2023) demonstrated significant glycemic improvements in Phase 2, with HbA1c reductions of up to -2.02% at the 12 mg dose over 36 weeks, along with improvements in fasting glucose, insulin sensitivity, and beta-cell function.[2] Body composition substudies confirmed that weight loss was primarily driven by fat mass reduction.[6]

        - Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/NAFLD) &mdash; A Phase 2a substudy by Sanyal et al. (2024) published in Nature Medicine demonstrated that the 8 mg and 12 mg doses normalized liver fat (<5%) in over 85% of participants, with relative liver fat reductions of up to 86% from baseline. This effect is linked to glucagon receptor-mediated increases in hepatic fatty acid oxidation and elevated beta-hydroxybutyrate biomarkers.[3]

        - Cardiovascular Disease (CVD) &mdash; The TRIUMPH-OUTCOMES Phase 3 trial is assessing whether retatrutide reduces the incidence of major adverse cardiovascular events (MACE) in adults with obesity and established atherosclerotic cardiovascular disease. Pre-trial data show dose-dependent heart rate increases that peak at 24 weeks before declining.[5][10]

        - Chronic Kidney Disease (CKD) &mdash; The TRANSCEND-CKD trial is investigating retatrutide's effects on kidney structure and function, including measured glomerular filtration rate (mGFR). Post-hoc analyses from Phase 2 data suggested potential renoprotective effects, including reduced albuminuria and improved renal hemodynamics over time.[7][9]

        - Knee Osteoarthritis (OA) &mdash; The TRIUMPH-4 Phase 3 trial evaluates retatrutide in patients with obesity and knee osteoarthritis. Results showed a significant reduction in WOMAC pain scores (up to 75.8% improvement) and improved physical function, alongside substantial weight loss.[5]

        - Obstructive Sleep Apnea (OSA) &mdash; Included within the TRIUMPH-1 and TRIUMPH-2 basket trials, research aims to determine retatrutide's efficacy in reducing the apnea-hypopnea index in patients with obesity.[5]

        - Obesity-Associated Cancer &mdash; Preclinical research by Marathe et al. (2025) demonstrated that retatrutide-induced weight loss reduced tumor engraftment, delayed tumor onset, and significantly attenuated tumor growth in pancreatic and lung cancer models, outperforming semaglutide. Antitumor effects persisted despite partial weight regain, suggesting durable systemic and tumor immune reprogramming.[14]

        - Diabetic Kidney Disease (DKD) &mdash; In preclinical studies, Ma et al. (2025) showed retatrutide demonstrated superior efficacy over liraglutide and tirzepatide in controlling risk factors associated with diabetic kidney disease in db/db mice, effectively mitigating inflammatory and fibrotic processes.[15]

      

      #### Clinical Efficacy Summary by Dose (Phase 2)

      
        DoseWeight Loss (48 wks, Obesity)HbA1c Reduction (36 wks, T2D)Evidence
        
          1 mg-8.7%&mdash;Jastreboff et al. (2023)[1]
          0.5 mg&mdash;-0.43%Rosenstock et al. (2023)[2]
          4 mg-17.1%~-1.3%[1][2]
          8 mg-22.8%~-1.9%[1][2]
          12 mg-24.2%-2.02%[1][2]

**Research Summary:**

### Preclinical & Clinical Research Summary

      #### Key Preclinical (Animal) Studies

      
        StudyModelKey FindingsRef
        
          Coskun et al. (2022)
Cell MetabolismDIO C57/Bl6 mice; 10 nmol/kg daily SC36.9% body weight loss (vs. 21.2% tirzepatide); 86.8% fat mass reduction; improved blood glucose, insulin, ALT, liver triglycerides; engages all three receptors in vivo[4]
          Urva et al. (2023)
Diabetes Obes. Metab.C57/Bl6 obese mice; 10 nmol/kg SCDose-dependent gastric emptying delay; chronic treatment attenuated GI slowing (tachyphylaxis); superior weight/food intake reduction vs. semaglutide alone[17]
          Ma et al. (2025)
EndocrineDiabetic db/db mice; 10 nmol/kg daily SC, 10 weeksSuperior efficacy over liraglutide and tirzepatide in reducing ALT, AST, cholesterol, triglycerides, LDL; mitigated inflammatory and fibrotic processes in diabetic kidney[15]
          Marathe et al. (2025)
NPJ Metab. Health Dis.Pancreatic and lung cancer models in obese miceReduced tumor engraftment; delayed tumor onset; greater tumor suppression than semaglutide; durable antitumor effects despite partial weight regain[14]
        
      

      #### Key Clinical (Human) Studies

      
        StudyPopulation / DesignKey ResultsRef
        
          Urva et al. (2022)
Lancet (Phase 1b)T2D patients; MAD, 0.5&ndash;12 mg SC weekly; RCTDose-dependent HbA1c and weight reductions; t1/2 ~6 days confirmed; GI AEs dose-related; well-tolerated overall[8]
          Jastreboff et al. (2023)
NEJM (Phase 2)Adults with obesity (no T2D); 1, 4, 8, 12 mg SC weekly; 48 wks; RCT-24.2% mean weight loss (12 mg); dose-dependent; not plateaued at 48 wks; GI AEs most common[1]
          Rosenstock et al. (2023)
Lancet (Phase 2)Adults with T2D; 0.5&ndash;12 mg SC weekly; 36 wks; RCTHbA1c -2.02% (12 mg); significant weight loss; improved insulin sensitivity; well-tolerated[2]
          Sanyal et al. (2024)
Nature Med. (Phase 2a)MASLD substudy; MRI-PDFF assessed liver fat; 48 wks>85% achieved liver fat normalization (<5%) at 8&ndash;12 mg doses; up to 86% relative liver fat reduction[3]
          TRIUMPH-4 (Phase 3, 2025)
Eli Lilly Press ReleaseObesity + knee OA; 9 & 12 mg SC weekly; 68 wksUp to 28.7% mean weight loss; WOMAC pain scores improved by up to 75.8%; first successful Phase 3 trial[5]
        
      

      #### Safety Profile Summary

      
        CategoryDetailIncidence / Notes
        
          Common GI AEsNausea, diarrhea, vomiting, constipation, decreased appetiteNausea up to 63% at highest doses; dose-dependent; most common during titration[12][13]
          Skin HyperesthesiaIncreased skin sensitivity, dysesthesia, "skin pain"Up to 7% (vs. 1% placebo) in Phase 2[10]
          Heart RateDose-dependent increase, peaking at 24 weeks before decliningMild to moderate arrhythmias reported[10]
          Serious AEsAcute pancreatitis (single cases); gallbladder disease; hypotensionSAE rate similar to placebo (~4&ndash;5%)[12]
          Hepatic SafetyNo hepatotoxicity signals; transient ALT/AST elevations resolvedMonitored in all trials[12]
        
      

      #### Dosage Summary

      
        SettingDoseRoute / ScheduleNotes
        
          In Vitro (EC50)0.0643 nM (GIPR), 0.775 nM (GLP-1R), 5.79 nM (GCGR)Cell cultureBiased toward GIP potency[4]
          Animal (Mice)10 nmol/kg dailySC injectionStandard efficacy dosing; t1/2 21 h in mice[4]
          Phase 1 (SAD)0.1&ndash;6 mg (single dose)SC injectionSafety/PK assessment[8]
          Phase 2 (Maintenance)1, 4, 8, 12 mgSC once weekly; titrated from 2 or 4 mgTitration by 2&ndash;4 mg every 4 weeks[1][2]
          Phase 3 (TRIUMPH)Target doses: 9 mg and 12 mgSC once weekly; initiated at 2 mgOngoing registrational trials[5]
        
      

      #### Pharmacokinetic Profile

      
        ParameterValueNotes
        
          Half-life (Human)~6 daysSupports once-weekly dosing[8]
          Half-life (Mouse)~21 hoursSingle 47 &mu;g/kg dose[4]
          Tmax12&ndash;72 hoursPost-SC dose in humans
          MetabolismHepatic proteolysis; fatty acid &beta;-oxidationNo CYP450 interaction
          Clearance (Mouse)11.22 mL/h/kgCD-1 mice
        
      

      &x26A0;&#xFE0F; Important Disclaimer

This product is sold strictly for in-vitro research and laboratory use only. It is not approved by the FDA for human consumption, medical use, diagnostic use, or veterinary use. Bodily introduction of any kind into humans or animals is strictly forbidden by law. All products are supplied as research chemicals only. The information provided here is compiled from peer-reviewed scientific literature and is intended solely for educational and informational purposes.

      About This Research Profile

This research profile was compiled from peer-reviewed sources including publications in the New England Journal of Medicine, The Lancet, Nature Medicine, Cell Metabolism, and other high-impact journals. All citations reference publicly available scientific literature. The profile is regularly reviewed and updated to reflect the latest research findings. Last reviewed: February 2026.

**Citations (17 references):**

- Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. New England Journal of Medicine, 389(6), 514-526, 2023. — https://pubmed.ncbi.nlm.nih.gov/37385337/
- Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet, 402(10401), 529-544, 2023. — https://doi.org/10.1016/S0140-6736(23)01053-X
- Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine, 30(7), 2037-2048, 2024. — https://doi.org/10.1038/s41591-024-03018-2
- Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK, Pirro V, Wainscott DB, Willard FS, Abernathy M, Morford L, Du Y, Benson C, Gimeno RE, Haupt A, Milicevic Z. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism, 34(9), 1234-1247.e9, 2022. — https://doi.org/10.1016/j.cmet.2022.07.013
- Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ, Wu Q, Lalonde A, Ahmad N, Bethel MA. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes, Obesity and Metabolism, 28(1), 83-93, 2026. — https://doi.org/10.1111/dom.70209
- Coskun T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C, Harris C. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. The Lancet Diabetes & Endocrinology, 13(8), 674-684, 2025. — https://doi.org/10.1016/S2213-8587(25)00092-0
- Heerspink HJL, Lu Z, Du Y, Duffin KL, Coskun T, Haupt A, Hartman ML. The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity. Kidney International Reports, 10(6), 1980-1992, 2025. — https://doi.org/10.1016/j.ekir.2025.03.049
- Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, Haupt A, Benson CT, Hernandez-Illas M, D'Alessio DA, Milicevic Z. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet, 400(10366), 1869-1881, 2022. — https://doi.org/10.1016/S0140-6736(22)02033-5
- Heerspink HJL, van Raalte DH, Bjornstad P, Bunck MC, Wu P, Tunali I, Milicevic Z, Koeneman L. Rationale, design and baseline characteristics of the TRANSCEND-CKD trial of retatrutide in patients with chronic kidney disease. Nephrology Dialysis Transplantation, gfaf230, 2025. — https://doi.org/10.1093/ndt/gfaf230
- Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide - A Game Changer in Obesity Pharmacotherapy. Biomolecules, 15(6), 796, 2025. — https://doi.org/10.3390/biom15060796
- Abdul-Rahman T, Roy P, Ahmed FK, Mueller-Gomez JL, Sarkar S, Garg N, Femi-Lawal VO, Wireko AA, Thaalibi HI, Hashmi MU, Dzebu AS, Banimusa SB, Sood A. The power of three: Retatrutide's role in modern obesity and diabetes therapy. European Journal of Pharmacology, 985, 177095, 2024. — https://doi.org/10.1016/j.ejphar.2024.177095
- Maharshi V, Singh S, Manjhi PK, Singh SK, Kumar A, Kumar R. Navigating retatrutide safety: comprehensive insights from systematic review and meta-analysis. Journal of Public Health and Development, 24(1), 318-338, 2026. — https://doi.org/10.55131/jphd/2026/240123
- Abouelmagd AA, Abdelrehim AM, Bashir MN, Abdelsalam F, Marey A, Tanas Y, Abuklish DM, Belal MM. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials. Proceedings (Baylor University Medical Center), 38(3), 291-303, 2025. — https://doi.org/10.1080/08998280.2025.2456441
- Marathe SJ, Grey EW, Bohm MS, Joseph SC, Ramesh AV, Cottam MA, et al. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression. NPJ Metabolic Health and Disease, 3(1), 10, 2025. — https://doi.org/10.1038/s44324-025-00054-5
- Ma J, Hu X, Zhang W, Tao M, Wang M, Lu W. Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice. Endocrine, 87(1), 159-169, 2025. — https://doi.org/10.1007/s12020-024-03998-8
- Tewari J, Qidwai KA, Tewari A, Kaur S, Tewari V, Maheshwari A. Efficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis. Expert Review of Clinical Pharmacology, 18(1-2), 51-66, 2025. — https://doi.org/10.1080/17512433.2025.2450254
- Urva S, O'Farrell L, Du Y, Loh MT, Hemmingway A, Qu H, Alsina-Fernandez J, Haupt A, Milicevic Z, Coskun T. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diabetes, Obesity and Metabolism, 25(11), 2784-2788, 2023. — https://doi.org/10.1111/dom.15167

**Storage & Handling:**

Lyophilized: -20°C to -80°C (stable 1–2 years); Reconstituted: aliquot and store at -20°C; avoid repeated freeze-thaw cycles; protect from moisture and light.

**Author:** Tamer Coskun, MD, PhD
Tamer Coskun, MD, PhD, is a senior researcher at Eli Lilly and Company (Indianapolis, IN, USA) and a key figure in the discovery and early development of retatrutide (LY3437943). He served as the lead author on the foundational 2022 publication in Cell Metabolism detailing the molecule's discovery, 

---

### Selank

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₃₃H₅₇N₁₁O₉ |
| Molecular Weight | 751.887 Da |
| CAS Number | 129954-34-3 |
| Sequence (3-letter) | Thr-Lys-Pro-Arg-Pro-Gly-Pro |
| Sequence (1-letter) | TKPRPGP |
| Amino Acids | 7 (heptapeptide) |
| Parent Molecule | Tuftsin (IgG fragment) + Pro-Gly-Pro stabilizer |
| Structural Type | Linear heptapeptide |
| Intranasal Bioavailability | 92.8% |
| Plasma Half-life | ~2 minutes (effects persist 20-24 hours) |

**Identifiers:**
- PubChem CID: 11765600
- InChI Key: JTDTXGMXNXBGBZ-UHFFFAOYSA-N
- Canonical SMILES: NCCCCC(C(=O)N1CCCC1C(=O)NC(C(=O)N2CCCC2C(=O)NCC(=O)N3CCCC3C(=O)O)CCCNC(=N)N)NC(C(C(C)O)N)=O
- IUPAC Name: 1-[2-({1-[2-({1-[6-Amino-2-(2-amino-3-hydroxy-butyrylamino)-hexanoyl]-pyrrolidine-2-carbonyl}-amino)-5-guanidino-pentanoyl]-pyrrolidine-2-carbonyl}-amino)-acetyl]-pyrrolidine-2-carboxylic acid

**Overview:**

### Overview

      Selank (TP-7) is a synthetic heptapeptide with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP). It was developed by the Institute of Molecular Genetics of the Russian Academy of Sciences in cooperation with the V.V. Zakusov Research Institute of Pharmacology.[2]

      Selank is derived from tuftsin (Thr-Lys-Pro-Arg), a naturally occurring tetrapeptide that constitutes a fragment of the heavy chain of human immunoglobulin G (IgG). The C-terminal Pro-Gly-Pro extension renders the molecule significantly more resistant to peptidase hydrolysis.[1]

      In experimental contexts, Selank exhibits anxiolytic and nootropic effects comparable to classical benzodiazepines (such as diazepam) but without their characteristic negative observations — sedation, muscle relaxation, amnesia, dependence, or withdrawal syndrome.[5][6]

      Regulatory records in the Russian Federation cite Selank's registration for research related to generalized anxiety disorders and neurasthenia.[3] It is not registered by the U.S. FDA, which has raised immunogenicity concerns related to compounding.[4] A notable pharmacokinetic feature is its exceptional intranasal bioavailability of 92.8% — rare for a peptide compound.[7]

**Mechanism of Action:**

### Mechanism of Action

      #### Dual Mechanism: GABA-A Modulation + Enkephalinase Inhibition

      Selank possesses a unique dual mechanism of action distinguishing it from classical anxiolytics:

      #### 1. GABA-A Receptor Positive Allosteric Modulation

      Selank acts as a positive allosteric modulator (PAM) of the GABA-A receptor. Its binding site is distinct from the classical benzodiazepine site, though partial overlap may exist.[8] This modulation enhances the affinity of the receptor for GABA, increasing inhibitory neurotransmission without producing sedation, amnesia, or muscle relaxation.[5]

      Selank administration significantly alters mRNA levels of GABA receptor subunits — Gabrb3, Gabre (epsilon), and Gabrq (theta) — as well as the GABA transporter Slc6a13 (GAT-2) in the frontal cortex. Dramatically, Gabre and Gabrq decreased approximately 20-fold at 1 hour, while Hcrt (orexin/hypocretin) decreased 25-fold then surged 128-fold by 3 hours.[9] This orexin rebound is hypothesized to explain the absence of sedation typical of benzodiazepines.

      #### 2. Enkephalinase Inhibition

      Selank competitively inhibits enzymes responsible for the degradation of enkephalins (endogenous opioid peptides), including aminopeptidases, carboxypeptidase H, and angiotensin-converting enzyme (ACE). The inhibitory effect has an IC50 of approximately 15–20 μM in human serum assays.[10] This extends the half-life of Leu-enkephalin, potentiating the body's natural stress-limiting and analgesic pathways.[11]

      #### BDNF/TrkB Signaling

      Selank rapidly elevates expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor TrkB. An increase in Bdnf mRNA is observed in the hippocampus as early as 90 minutes, with protein levels increasing by 24 hours.[12]

      #### Monoamine Neurotransmitter Modulation

      Selank induces region-specific changes in monoamine metabolism:

      
        - Serotonin: Increased 5-HIAA (metabolite) in hypothalamus and brainstem within 30 minutes to 2 hours[13]

        - Norepinephrine: Increased in the hypothalamus[13]

        - Dopamine: Strain-dependent — decreased metabolites in high-anxiety (BALB/c) mice, increased in low-anxiety (C57BL/6) mice[13]

      

      #### Immunomodulation

      Selank modulates IL-6 expression, normalizes the Th1/Th2 cytokine balance, and induces interferon-alpha (IFN-α) secretion.[14]

      #### Receptor Selectivity

      Importantly, radioreceptor assays show that Selank does not directly displace ligands from benzodiazepine, dopamine (D2), serotonin (5-HT2), or opioid (μ, δ) receptors. Its effects on these systems are downstream or allosteric.[8] However, the opioid antagonist naloxone blocks Selank's anxiolytic effects, confirming the enkephalin system's involvement.[15]

**Research Applications:**

### Research Applications

      In laboratory research, Selank is investigated in multiple experimental paradigms:

      
        - Anxiety and Generalized Anxiety Models — Registered in the Russian Federation for research related to generalized anxiety disorders and neurasthenia. Experimental readouts demonstrate anxiolytic effects comparable to benzodiazepines without sedation, dependence, or withdrawal.[5][6]

        - Cognitive Enhancement / Nootropic Paradigms — Studied for effects on memory consolidation and learning. A single injection increased memory trace stability for up to 30 days via serotonin metabolism activation.[13]

        - Alcohol Withdrawal Models — Eliminated withdrawal-induced anxiety (EPM open arm time p[16]

        - Opioid Withdrawal Models — Reduced mean morphine withdrawal index by 39.6%, significantly attenuating convulsive reactions, ptosis, and posture disorders (p[17]

        - Immunomodulation and Antiviral Activity — Demonstrated antiviral effects against Influenza A (H3N2) both in vivo and in vitro. Induced IFN-α secretion and normalized Th1/Th2 cytokine balance.[14]

        - Gene Expression Modulation — Administration altered expression of 45 genes at 1 hour in frontal cortex, including GABAergic receptor subunits and orexin/hypocretin (128-fold rebound at 3 hours).[9]

        - Gastric Protection Models — Exhibited protective effects against stress- and ethanol-induced gastric mucosal injury, increasing mucosal resistance to ulcerogenic factors.[2]

        - Gut Microbiota and Stress — Prevented stress-induced decreases in obligate microflora, reduced corticosterone levels, and attenuated colon wall pathomorphological changes.[18]

**Research Summary:**

### Preclinical Research Summary

      #### Animal Studies

      
        ModelSpeciesKey FindingsRef
        
          Anxiety (UCMS)Wistar ratsSelank+Diazepam → OA time 8.9× higher than saline; prevented stress deterioration[19]
          Anxiety PhenotypesBALB/c vs C57BL/6 miceSelective anxiolytic in high-anxiety BALB/c; strain-dependent monoamine modulation[13]
          Primate NeurosisMonkeysEliminated fear and aggression; increased exploratory activity, long-lasting effect[2]
          Alcohol WithdrawalOutbred rats↑ EPM open arms (p[16]
          Morphine WithdrawalOutbred rats↓ withdrawal index 39.6%; ↑ tactile sensitivity 9×; attenuated convulsions (p[17]
          Memory TraceWistar rats30-day memory stability via serotonin metabolism activation[13]
          GABAergic GenesWistar rats45 genes altered at 1h; Gabre ↓20×, Hcrt ↑128× at 3h (explains no sedation)[9]
          BDNF ExpressionRats↑ Bdnf mRNA at 3h; ↑ BDNF protein at 24h[12]
          Gut MicrobiotaWistar ratsPrevented stress-induced microflora changes; ↓ corticosterone[18]
          Influenza (H3N2)Mice↑ survival; IFN-α induction; Th1/Th2 normalization[14]
        
      

      #### Clinical Studies / Human Data

      
        StudyDesignn=Key OutcomeRef
        
          Zozulya 2008 (Phase II)RCT vs medazepam62Comparable anxiolytic efficacy to medazepam; + anti-asthenic/psychostimulant effects; onset 1-3 days[5]
          Medvedev 2015 (Add-on)Add-on to Phenazepam70Earlier onset of benzo effects; decreased attention/memory impairment from Phenazepam[20]
          Medvedev 2014 (Comparison)vs Phenazepam60Pronounced anxiolytic + mild nootropic; effects persist 1 week post-dose[21]
          Elderly Vascular StudyClinical—Reduced anxiety, improved concentration, increased reaction speed in elderly[3]
          Uchakina 2008 (Immune)Immunological—Completely suppressed IL-6 gene expression in anxious subjects; normalized Th1/Th2 balance[14]
        
      

      #### Pharmacokinetic Parameters

      
        ParameterValueRef
        
          Intranasal Bioavailability92.8% (exceptional for a peptide)[7]
          Plasma Half-life~2 minutes[7]
          Duration of Experimental Effects20–24 hours (trigger mechanism)[7]
          CNS PenetrationDetected in brain within 2 minutes (intranasal)[7]
          GABA-A ModulationPositive allosteric modulator (non-BZD site)[8]
          Enkephalinase IC₅₀15–20 μM (human serum)[10]
        
      

      #### Comparison: Selank vs. Benzodiazepines

      
        FeatureSelankBenzodiazepines
        
          Anxiolytic EffectComparable (Phase II)Established
          SedationNoneCommon
          Muscle RelaxationNoneCommon
          Cognitive ImpairmentNone (nootropic effect)Amnesia risk
          DependenceNone observedHigh risk
          WithdrawalNone observedSignificant risk
          MechanismGABA-A PAM + enkephalinaseGABA-A BZD site
          Additional EffectsNootropic + immunomodulatoryNone
        
      

      #### Comparison: Selank vs. Semax

      
        FeatureSelankSemax
        
          Parent MoleculeTuftsin (IgG fragment)ACTH(4-7)
          SequenceTKPRPGP (7 aa)MEHFPGP (7 aa)
          Primary FocusAnxiolytic / immunomodulationNootropic / neuroprotection
          Unique MechanismGABA-A PAM + enkephalinaseMC4/MC5 antagonist + BDNF/TrkB
          PGP StabilizerYesYes
          DeveloperIMG RAS + Zakusov InstituteIMG RAS
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (25 references):**

- Kolomin TA, Shadrina M, Slominsky P, Limborska SA, Myasoedov NF. A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neuroscience & Medicine. 2013;4(4):223–252. — https://doi.org/10.4236/nm.2013.44035
- Vyunova TV, Andreeva LA, Shevchenko KV, Myasoedov NF. Peptide-based Anxiolytics: The Molecular Aspects of Heptapeptide Selank Biological Activity. Protein & Peptide Letters. 2018;25(10):914–923. — https://pubmed.ncbi.nlm.nih.gov/30259812/
- Medvedev VE, Tereshchenko ON, Kost NV, et al. Optimization of the treatment of anxiety disorders with selank. Zhurnal Nevrologii i Psikhiatrii. 2015;115(6):33–40. — https://pubmed.ncbi.nlm.nih.gov/26356395/
- U.S. Food and Drug Administration. Bulk Drug Substances Used in Compounding Under Section 503B. FDA Compounding Database. 2023. — https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding
- Zozulya AA, Neznamov GG, Syunyakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zhurnal Nevropatologii i Psikhiatrii. 2008;108(4):38–48. — https://pubmed.ncbi.nlm.nih.gov/18551794/
- Kozlovskii II, Danchev ND. The optimizing action of the synthetic peptide Selank on a conditioned active avoidance reflex in rats. Neuroscience and Behavioral Physiology. 2003;33(7):639–643. — https://pubmed.ncbi.nlm.nih.gov/14552528/
- Kolomin TA, Agapova T, Agniullin YV, et al. Changes in the Transcription Profile of the Hippocampus in Response to Administration of the Tuftsin Analog Selank. Neuroscience and Behavioral Physiology. 2014;44(8):849–855. — https://doi.org/10.1007/s11055-014-9992-4
- V'yunova TV, Andreeva LA, Shevchenko KV, et al. Peptide regulation of specific ligand-receptor interactions of GABA with the plasma membranes of nerve cells. Neurochemical Journal. 2014;8(4):259–264. — https://doi.org/10.1134/S1819712414040114
- Volkova A, Shadrina M, Kolomin T, et al. Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission. Frontiers in Pharmacology. 2016;7:31. — https://pubmed.ncbi.nlm.nih.gov/26941647/
- Kost NV, Sokolov OY, Gabaeva MV, et al. Semax and Selank Inhibit the Enkephalin-Degrading Enzymes of Human Serum. Russian Journal of Bioorganic Chemistry. 2001;27(3):180–183. — https://doi.org/10.1023/A:1011373002885
- Zozulya AA, Kost NV, Sokolov OY, et al. The Inhibitory Effect of Selank on Enkephalin-Degrading Enzymes as a Possible Mechanism of Its Anxiolytic Activity. Bull Exp Biol Med. 2001;131(4):315–317. — https://pubmed.ncbi.nlm.nih.gov/11550015/
- Inozemtseva LS, Karpenko EA, Dolotov OV, et al. Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo. Doklady Biological Sciences. 2008;421:241–243. — https://pubmed.ncbi.nlm.nih.gov/18841819/
- Narkevich VB, Kudrin VS, Klodt PM, et al. Effects of Selank on monoamine neurotransmitters in the brain of BALB/c and C57BL/6 mice. Bull Exp Biol Med. 2008;145(1):68–71. — https://pubmed.ncbi.nlm.nih.gov/19145306/
- Uchakina ON, Uchakin PN, Miasoedov NF, et al. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zhurnal Nevrologii i Psikhiatrii. 2008;108(5):71–75. — https://pubmed.ncbi.nlm.nih.gov/18577961/
- Kozlovskii II, Andreeva LA, Kozlovskaya MM. The role of the endogenous opioid system in the anxiolytic action of Selank. Bull Exp Biol Med. 2012;153(5):728–730. — https://pubmed.ncbi.nlm.nih.gov/23113285/
- Kolik LG, Nadorova AV, Kozlovskaya MM. Efficacy of Peptide Anxiolytic Selank during Modeling of Withdrawal Syndrome in Rats with Stable Alcoholic Motivation. Bull Exp Biol Med. 2014;157(1):61–65. — https://pubmed.ncbi.nlm.nih.gov/24909720/
- Konstantinopolsky MA, Kolik LG, Chernyakova IV. Selank, a Peptide Analog of Tuftsin, Attenuates Aversive Signs of Morphine Withdrawal in Rats. Bull Exp Biol Med. 2022;173(6):730–733. — https://pubmed.ncbi.nlm.nih.gov/36334183/
- Mukhina AY, et al. Effects of Selank on intestinal microbiota and stress-induced changes. Russian Journal of Physiology. 2019/2020. — https://pubmed.ncbi.nlm.nih.gov/32558368/
- Kasian A, Kolomin T, Andreeva L, et al. Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats. Behavioural Neurology. 2017;2017:5091027. — https://pubmed.ncbi.nlm.nih.gov/29317790/
- Kolik LG, Nadorova AV, Antipova TA, Durnev AD. Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content. Bull Exp Biol Med. 2019;167(5):641–644. — https://pubmed.ncbi.nlm.nih.gov/31598885/
- Medvedev VE, Tereshchenko ON, Israelian AI, et al. A comparison of the anxiolytic effect and tolerability of selank and phenazepam. Zhurnal Nevrologii i Psikhiatrii. 2014;114(7):17–22. — https://pubmed.ncbi.nlm.nih.gov/25176280/
- Semenova TP, Kozlovskii II, Zakharova NM, Kozlovskaya MM. Experimental optimization of learning and memory processes by selank. Eksperimental'naia i Klinicheskaia Farmakologiia. 2010;73(8):2–5. — https://pubmed.ncbi.nlm.nih.gov/21049676/
- Filatova E, Kasian A, Kolomin T, et al. GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells. Frontiers in Pharmacology. 2017;8:89. — https://pubmed.ncbi.nlm.nih.gov/28280470/
- Kolomin TA, Shadrina M, Andreeva LA, et al. Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank. Regulatory Peptides. 2011;170(1-3):18–23. — https://pubmed.ncbi.nlm.nih.gov/21616098/
- Andreeva LA, Nagaev IY, Mezentseva MV, et al. Antiviral properties of structural fragments of the peptide Selank. Doklady Biological Sciences. 2010;431:79–82. — https://pubmed.ncbi.nlm.nih.gov/20506858/

**Storage & Handling:**

Store lyophilized powder at 4°C. Reconstituted solution: 2-8°C, stable ~1 month. Avoid agitation.

**Author:** Dr. Nikolay F. Myasoedov
Nikolay F. Myasoedov is affiliated with the Institute of Molecular Genetics, Russian Academy of Sciences, and the Department of Chemistry of Physiologically Active Compounds. He headed the research team that developed Selank (and the related compound Semax) as synthetic peptides based on natural reg

---

### Semaglutide

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C187H291N45O59 |
| molecular_weight | 4113.58 g/mol |
| synonyms | Ozempic, Wegovy, Rybelsus (Generic references) |
| cas_number | 910463-68-2 |
| sequence | H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(AEEAc-AEEAc-γ-Glu-17-carboxyheptadecanoyl)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH |
| pubchem_cid | 56843331 |

**Overview:**

### Research Overview

      Semaglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with 94% structural homology to native human GLP-1. It features an aminoisobutyric acid (Aib) substitution at position 8 for DPP-4 resistance and a C18 fatty diacid chain linked via a spacer at Lys26, enabling non-covalent albumin binding that extends its half-life to approximately 7 days.[1][2]

      Developed by Novo Nordisk, semaglutide was approved by the FDA for type 2 diabetes (Ozempic, 2017; Rybelsus, 2019) and chronic weight management (Wegovy, 2021). It has since become one of the most extensively studied peptide therapeutics in modern pharmacology, with large-scale cardiovascular outcomes trials (SUSTAIN, PIONEER, SELECT, STEP, FLOW) enrolling over 40,000 participants collectively.[3][4][5]

      Beyond glycemic control and weight loss, research has identified cardiovascular risk reduction (20% MACE reduction in SELECT trial), renal protection (slowed kidney disease progression in FLOW trial), and emerging signals in MASH/NASH, Alzheimer's disease, addiction, and obstructive sleep apnea.[5][6][7]

**Mechanism of Action:**

### Mechanism of Action

      Semaglutide selectively activates the GLP-1 receptor (GLP-1R), a Class B1 G protein-coupled receptor expressed on pancreatic beta cells, hypothalamic neurons, cardiomyocytes, and GI smooth muscle.[1]

      #### Key Downstream Effects

      
        Target TissueMechanismClinical Effect
        
          Pancreatic Beta CellscAMP/PKA activation → glucose-dependent insulin secretionImproved glycemic control; low hypoglycemia risk
          Pancreatic Alpha CellsSuppresses glucagon secretion (glucose-dependent)Reduced hepatic glucose output
          HypothalamusActivates POMC/CART neurons; inhibits NPY/AgRPAppetite suppression; reduced caloric intake
          GI TractDelays gastric emptying via vagal afferentsIncreased satiety; reduced postprandial glucose
          CardiovascularAnti-inflammatory, anti-atherosclerotic, endothelial protection20% MACE reduction (SELECT trial)
        
      
      The C18 fatty diacid acylation enables reversible albumin binding, creating a circulating depot that extends the half-life from ~2 minutes (native GLP-1) to ~168 hours, enabling once-weekly dosing.[2][8]

**Research Summary:**

### Research Summary

      #### Landmark Clinical Trials

      
        TrialNKey FindingRef
        
          SUSTAIN-63,29726% MACE reduction vs placebo in T2D[3]
          STEP 11,96114.9% body weight loss (2.4 mg/wk) vs 2.4% placebo[4]
          SELECT17,60420% MACE reduction in overweight/obese without diabetes[5]
          FLOW3,53324% reduction in kidney disease progression in T2D + CKD[6]
          PIONEER 63,183Oral semaglutide non-inferior for CV safety[9]
        
      
      Important Disclaimer

This product is sold strictly for in-vitro research and laboratory use only. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

      About This Research Profile

This research profile was compiled from peer-reviewed sources including the New England Journal of Medicine, The Lancet, and regulatory documents. ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (12 references):**

- Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry, 58(18), 7370-7380, 2015. — https://doi.org/10.1021/acs.jmedchem.5b00726
- Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive ethinylestradiol/levonorgestrel. Journal of Clinical Pharmacology, 55(5), 497-504, 2015. — https://pubmed.ncbi.nlm.nih.gov/25475122/
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine, 375(19), 1834-1844, 2016. — https://doi.org/10.1056/NEJMoa1607141
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine, 384(11), 989-1002, 2021. — https://doi.org/10.1056/NEJMoa2032183
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). New England Journal of Medicine, 389(24), 2221-2232, 2023. — https://doi.org/10.1056/NEJMoa2307563
- Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW). New England Journal of Medicine, 391(2), 109-121, 2024. — https://doi.org/10.1056/NEJMoa2403347
- Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New England Journal of Medicine, 384(12), 1113-1124, 2021. — https://doi.org/10.1056/NEJMoa2028395
- Knop FK, Aroda VR, do Vale RD, et al. Oral semaglutide 50 mg taken once daily in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet, 402(10403), 705-719, 2023. — https://doi.org/10.1016/S0140-6736(23)01185-6
- Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (PIONEER 6). New England Journal of Medicine, 381(9), 841-851, 2019. — https://doi.org/10.1056/NEJMoa1901118
- Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes (PIONEER 7). JAMA, 321(15), 1466-1480, 2019. — https://doi.org/10.1001/jama.2019.2942
- Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity (STEP 4). JAMA, 325(14), 1414-1425, 2021. — https://doi.org/10.1001/jama.2021.3224
- Wadden TA, Bailey TS, Billings LK, et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity (STEP 3). JAMA, 325(14), 1403-1413, 2021. — https://doi.org/10.1001/jama.2021.1831

**Storage & Handling:**

Store at 2°C to 8°C (36°F to 46°F).

---

### Semax

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₃₇H₅₁N₉O₁₀S |
| Molecular Weight | 813.93 Da |
| CAS Number | 80714-61-0 |
| Sequence (3-letter) | Met-Glu-His-Phe-Pro-Gly-Pro |
| Sequence (1-letter) | MEHFPGP |
| Amino Acids | 7 (heptapeptide) |
| Parent Molecule | ACTH(4-7) + Pro-Gly-Pro stabilizer |
| Stability | 20× more stable than native ACTH(4-10) |
| Hormonal Activity | None — devoid of corticotropic activity |
| Structural Type | Linear heptapeptide, all L-amino acids |

**Identifiers:**
- PubChem CID: 122178
- InChI Key: AFEHBIGDWIGTEH-CXFOGXNKSA-N
- Canonical SMILES: O=C(N[C@@H](CCC(O)=O)C(N[C@@H](CC1=CNC=N1)C(N[C@@H](CC2=CC=CC=C2)C(N3[C@@H](CCC3)C(NCC(N4[C@@H](CCC4)C(O)=O)=O)=O)=O)=O)=O)[C@H](CCSC)N
- IUPAC Name: (2S)-1-[2-{[(2S)-1-[(2S)-2-{[2-{[(2S)-2-{[(2S)-2-amino-4-methylsulfanylbutanoyl]amino}-4-carboxybutanoyl]amino}-3-(1H-imidazol-5-yl)propanoyl]amino}-3-phenylpropanoyl]pyrrolidine-2-carbonyl}amino}acetyl]pyrrolidine-2-carboxylic acid

**Overview:**

### Overview

      Semax (ACTH 4-7-PGP) is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro. It was designed by modifying the ACTH(4-7) fragment with a C-terminal Pro-Gly-Pro (PGP) tripeptide to enhance enzymatic stability.[2] This modification renders the compound approximately 20 times more resistant to peptidase degradation compared to the native ACTH(4-10) fragment, extending its experimental duration from minutes to 20–24 hours.[3]

      The compound is completely devoid of the hormonal corticotropic activity associated with full-length ACTH, meaning it does not stimulate adrenal cortisol production.[4] Regulatory records in the Russian Federation cite Semax's registration as a pharmaceutical on the "Vital and Essential Drugs" list for investigations related to stroke, cognitive disorders, and optic nerve conditions.[5] It is not registered by the U.S. FDA and has been flagged for immunogenicity concerns in compounding contexts.[6]

      Semax was originally developed by the Institute of Molecular Genetics of the Russian Academy of Sciences (IMG RAS).[7] Upon enzymatic degradation, the PGP tripeptide fragment possesses its own independent experimental activity, including neuroprotective and anti-ulcer effects, contributing to the overall profile of the compound.[8]

**Mechanism of Action:**

### Mechanism of Action

      #### Receptor Targets and Binding

      Specific binding sites for Semax have been identified in basal forebrain membranes. Binding is reversible, specific, and time-dependent, with a dissociation constant (Kd) of 2.4 ± 1.0 nM and maximal binding capacity (Bmax) of 33.5 ± 7.9 fmol/mg protein.[9] This binding strictly requires calcium ions (Ca²⁺) and is blocked by manganese ions (Mn²⁺), characteristic of G-protein-coupled receptor interactions.[10]

      In receptor assays, Semax acts as a competitive antagonist of α-melanocyte-stimulating hormone (α-MSH) at the MC4 and MC5 melanocortin receptors. No antagonism was observed at MC3.[11] Additionally, Semax inhibits enzymes responsible for enkephalin degradation (IC50 = 10 μM).[12]

      #### BDNF/TrkB Signaling Cascade

      Semax stimulates tyrosine phosphorylation of TrkB receptors (the high-affinity receptor for BDNF), producing a 1.5–1.6-fold increase in TrkB phosphorylation in the hippocampus within 3 hours of administration.[9] In glial cell cultures, BDNF mRNA increased 8-fold and NGF mRNA 5-fold within 30 minutes.[13] In vivo, Semax increased hippocampal BDNF protein by 1.4-fold and exon III BDNF mRNA by 3-fold.[14]

      #### Neurotransmitter Modulation

      Semax activates the dopaminergic and serotonergic systems. It increases extracellular levels of 5-HIAA (a serotonin metabolite) in the striatum by approximately 25%.[1] While it does not alter basal dopamine levels alone, it significantly potentiates dopamine release induced by D-amphetamine.[1] Semax also regulates intracellular calcium homeostasis, preventing Ca²⁺ deregulation under glutamate excitotoxicity conditions.[10]

      #### Gene Expression and Transcription

      Genome-wide transcriptional analysis following ischemia-reperfusion demonstrated that Semax modulates 394 differentially expressed genes. It upregulates neurotransmission-related genes including Gpr6, Drd2, Hes5, and Gpr88, while downregulating pro-inflammatory genes such as Il1b, Il6, and Ccl6.[15][16]

      #### Pharmacokinetic Paradox

      Despite a relatively short plasma elimination half-life of approximately 1–2 hours, the experimental effects of a single intranasal dose persist for 20–24 hours.[5] Intranasal bioavailability is reported at 60–70%, with rapid CNS penetration across the blood-brain barrier.[17]

**Research Applications:**

### Research Applications

      In laboratory research, Semax is utilized in multiple experimental paradigms:

      
        - Ischemic Stroke and TIA Models — Registered in the Russian Federation for investigations related to acute ischemic stroke. Experimental readouts involve suppression of inflammatory genes and activation of neurotransmitter gene networks in the penumbra zone.[15][16]

        - Cognitive Enhancement / Nootropic Paradigms — Studied for effects on memory consolidation and selective attention. In experimental protocols, a single intranasal dose produced measurable cognitive effects lasting 20–24 hours.[18]

        - Optic Nerve Investigations — Experimental readouts involving optic nerve atrophy and glaucomatous neuropathy models demonstrate improved visual acuity, expanded visual field, and increased optic nerve electric sensitivity.[19]

        - Neuroprotection and Oxidative Stress — In neuronal cultures, Semax demonstrated anti-apoptotic effects, protecting against glutamate neurotoxicity and oxidative stress. It contributes to mitochondrial stability and upregulates neurotrophin expression (BDNF, NGF).[9][14]

        - Stress and Anxiety Models — In rodent models of chronic stress, Semax exhibited anxiolytic effects linked to modulation of dopaminergic and serotonergic systems and normalization of hippocampal BDNF levels. Corticosterone levels decreased 28–34%.[20]

        - Alzheimer's Disease Models — In APP/PS1 transgenic mice, intranasal Semax reduced amyloid plaque count in cortex by 2.8-fold and hippocampus by 2.6-fold (p[21]

        - Spinal Cord Injury Models — Improved functional recovery scores via μ-opioid receptor (Oprm1) / USP18 / FTO pathway, inhibiting lysosomal membrane permeabilization and pyroptosis.[22]

        - Gastric Ulcer Investigations — In a comparative study, ulcer healing was observed in 89.5% of subjects receiving Semax vs. 30.8% in the control group at day 14.[23]

        - Immune System Modulation — Transcriptional analyses indicate Semax influences immunoglobulin and chemokine gene expression, with potential antiviral activity observed in experimental influenza models.[16]

**Research Summary:**

### Preclinical Research Summary

      #### Animal Studies

      
        ModelSpeciesKey FindingsRef
        
          Alzheimer's (APP/PS1)Transgenic micePlaque reduction 2.8× cortex, 2.6× hippocampus; cognitive restoration (p<0.0001)[21]
          Ischemic Stroke (tMCAO)Wistar rats394 DEGs modulated; vascularization ↑1.25×, neuroglial proliferation ↑1.4×[15]
          Chronic StressWistar ratsCorticosterone ↓28–34%; anxiety reduced at 50–150 μg/kg[20]
          Spinal Cord InjuryC57BL/6 miceImproved Basso scores; μ-opioid / USP18 / FTO pathway[22]
          Cognitive EnhancementWistar rats1.4× hippocampal BDNF protein; 3× exon III BDNF mRNA; accelerated learning[14]
          Dopaminergic SystemC57BL/6 mice+25% striatal 5-HIAA; potentiated amphetamine-induced DA release[1]
          OphthalmicWistar ratsRetinal microcirculation ↑ to 671.7 PU; improved ERG parameters[24]
          Maternal DeprivationWhite ratsNormalized anxiety from early-life stress; compensated body weight loss[25]
        
      

      #### Clinical Studies / Human Data

      
        StudyDesignn=Key OutcomeRef
        
          Kaplan 1996Volunteers—Improved memory and attention lasting 20–24 hours[18]
          Russian Patent 1995Multi-condition303Enhanced selective attention, motivation, adaptive capability[4]
          Gusev 2005Clinical187Reduced stroke/TIA risk; stabilized disease progression[5]
          Gusev 1997/2018Clinical—Accelerated functional recovery, decreased inflammation (IL-10, CRP)[7]
          Polunin 2000Comparative—Improved visual acuity, expanded visual field[19]
          Kurysheva 2001Comparative—Superior to traditional neuroprotective protocols for glaucomatous neuropathy[19]
          Ivanikov 2002Comparative—89.5% healing (Semax) vs 30.8% (control) at day 14[23]
          Serdiuk 2007Clinical27Improved quality of life, mood, and cognition[5]
        
      

      #### Pharmacokinetic Parameters

      
        ParameterValueRef
        
          Intranasal Bioavailability60–70%[17]
          Plasma Half-life~1–2 hours[17]
          Duration of Experimental Effects20–24 hours[5]
          BBB PenetrationRapid CNS distribution[17]
          Receptor Binding (Kd)2.4 ± 1.0 nM (basal forebrain)[9]
          MC4/MC5 ActivityCompetitive antagonist (α-MSH)[11]
          Enkephalinase InhibitionIC₅₀ = 10 μM[12]
        
      

      #### Comparison with Related Compounds

      
        FeatureSemaxSelank
        
          Parent MoleculeACTH(4-7)Tuftsin
          SequenceMEHFPGP (7 aa)TKPRPGP (7 aa)
          Primary FocusNootropic / neuroprotectionAnxiolytic / immunomodulation
          BDNF InductionStrong (8× mRNA)Moderate
          Hormonal ActivityNoneNone
          PGP StabilizerYesYes
          Russian RegistrationYes — stroke, cognition, optic nerveYes — anxiety disorders
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (23 references):**

- Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS. Semax, an ACTH(4-10) Analogue with Nootropic Properties, Activates Dopaminergic and Serotoninergic Brain Systems in Rodents. Neurochemical Research. 2005;30(12):1493–1500. — https://pubmed.ncbi.nlm.nih.gov/16362768/
- Potaman VN, Alfeeva LY, Kamensky AA, Levitzkaya NG, Nezavibatko VN. N-terminal degradation of ACTH(4-10) and its synthetic analog semax by the rat blood enzymes. Biochem Biophys Res Commun. 1991;176(2):741–746. — https://pubmed.ncbi.nlm.nih.gov/1851599/
- Ashmarin IP, Nezavibatko VN, Levitskaya NG, Koshelev VB, Kamensky AA. Design and investigation of an ACTH(4-10) analogue lacking D-amino acids and hydrophobic radicals. Neuroscience Research Communications. 1995;16(2):105–112. — https://pubmed.ncbi.nlm.nih.gov/8460093/
- Ashmarin IP, Nezavibatko VN, Myasoedov NF, et al. A nootropic adrenocorticotropin analog 4-10-semax (15 years experience in its design and study). Zhurnal Vysshei Nervnoi Deiatelnosti. 1997;47(2):420–430. — https://pubmed.ncbi.nlm.nih.gov/9173040/
- Gusev EI, Skvortsova VI, Chukanova EI. Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency. Zhurnal Nevrologii i Psikhiatrii. 2005;105(2):35–40. — https://pubmed.ncbi.nlm.nih.gov/15792139/
- U.S. Food and Drug Administration. Bulk Drug Substances Used in Compounding Under Section 503B. FDA Compounding Database. 2023. — https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding
- Gusev EI, Skvortsova VI, Myasoedov NF, et al. Effectiveness of Semax in acute period of hemispheric ischemic stroke. Zhurnal Nevrologii i Psikhiatrii. 1997;97(6):26–34. — https://pubmed.ncbi.nlm.nih.gov/9381510/
- Kolomin TA, Shadrina M, Slominsky P, Limborska SA, Myasoedov NF. A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neuroscience and Medicine. 2013;4(4):223–252. — https://doi.org/10.4236/nm.2013.44035
- Dolotov OV, Karpenko EA, Seredenina TS, et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of BDNF protein in rat basal forebrain. J Neurochem. 2006;97(Suppl 1):82–86. — https://pubmed.ncbi.nlm.nih.gov/16635252/
- Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research. 2006;1117(1):54–60. — https://pubmed.ncbi.nlm.nih.gov/16934792/
- Levitskaya NG, Glazova NY, Sebentsova EA, et al. Investigation of the Spectrum of Physiological Activities of the Heptapeptide Semax. Neurochemical Journal. 2008;2(1–2):95–101. — https://doi.org/10.1134/S1819712408010182
- Shadrina MI, Dolotov OV, Grivennikov IA, et al. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax. Neuroscience Letters. 2001;308(2):115–118. — https://pubmed.ncbi.nlm.nih.gov/11457573/
- Filippenkov IB, Stavchansky VV, Denisova AE, et al. Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Following Cerebral Ischaemia–Reperfusion in Rats. Genes. 2020;11(6):681. — https://pubmed.ncbi.nlm.nih.gov/32575463/
- Medvedeva EV, Dmitrieva VG, Povarova OV, et al. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis. BMC Genomics. 2014;15:228. — https://pubmed.ncbi.nlm.nih.gov/24661662/
- Stavchansky VV, Yuzhakov VV, Botsina AY, et al. The Effect of Semax and Its C-End Peptide PGP on the Morphology and Proliferative Activity of Rat Brain Cells During Experimental Ischemia. J Mol Neurosci. 2011;45(2):177–185. — https://pubmed.ncbi.nlm.nih.gov/20640535/
- Kaplan AY, Kochetova AG, Nezavibatko VN, Ryasina TV, Ashmarin IP. Synthetic ACTH analogue Semax displays nootropic-like activity in humans. Neuroscience Research Communications. 1996;19(2):115–123. — https://doi.org/10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC166>3.0.CO;2-B
- Polunin GS, Nurieva SM, Bayandin DL, Sheremet NL. Evaluation of therapeutic effect of new Russian peptide drug Semax in optic nerve disease. Vestnik Oftalmologii. 2000;116(1):15–18. — https://pubmed.ncbi.nlm.nih.gov/10741256/
- Vorvul AO, Bobyntsev II, Medvedeva OA, et al. Effects of Semax in conditions of acute and chronic social stress. Zhurnal Vysshei Nervnoi Deiatelnosti. 2021;71(4):560–570. — https://pubmed.ncbi.nlm.nih.gov/34553863/
- Radchenko AI, Kuzubova EV, Apostol AA, et al. The Potential of the Peptide Drug Semax and Its Derivative for Correcting Pathological Impairments in the Animal Model of Alzheimer's Disease. Acta Naturae. 2025;17(4):110–120. — https://pubmed.ncbi.nlm.nih.gov/39959655/
- Liu Y, et al. Semax improves spinal cord injury via μ-opioid receptor targeting USP18-mediated FTO deubiquitination. Front Cell Neurosci. 2025. — https://pubmed.ncbi.nlm.nih.gov/39896901/
- Ivanikov IO. Novel approach to treatment of refractory peptic ulcers using intranasal Semax. Clinical Gastroenterology. 2002. — https://pubmed.ncbi.nlm.nih.gov/12094072/
- Stavchansky VV, Yuzhakov VV, Sevan'kaeva LE, et al. Melanocortin Derivatives Induced Vascularization and Neuroglial Proliferation in the Rat Brain under Conditions of Cerebral Ischemia. Curr Issues Mol Biol. 2024;46(3):2071–2092. — https://pubmed.ncbi.nlm.nih.gov/38534760/
- Volodina MA, Sebentsova EA, Glazova NY, et al. Semax Attenuates the Influence of Neonatal Maternal Deprivation on the Behavior of Adolescent White Rats. Bull Exp Biol Med. 2012;152(5):560–563. — https://pubmed.ncbi.nlm.nih.gov/22803094/

**Storage & Handling:**

Store lyophilized powder at -20°C. Reconstituted solution: 2-8°C, stable 4-6 weeks. Protect from light.

**Author:** Dr. Nikolay F. Myasoedov
Nikolay F. Myasoedov is affiliated with the Institute of Molecular Genetics, Russian Academy of Sciences, and the National Research Center Kurchatov Institute. He is credited with the synthesis of Semax and has conducted extensive research into its neuroprotective mechanisms, specifically its abilit

---

### Sermorelin

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₁₄₉H₂₄₆N₄₄O₄₂S |
| molecular_weight | 3,357.88 Da |
| synonyms | Sermorelin acetate, Geref, GRF 1-29 NH₂, GHRH(1-29), Growth Hormone-Releasing Factor (1-29) amide, Somatotropin-releasing-hormone(1-29)amide |
| cas_number | 86168-78-7 |
| sequence | YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH₂ (29 aa) |
| pubchem_cid | 16129620 / 16132413 |
| monoisotopic_mass | 3,355.818 Da |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | N/A |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 16129620 / 16132413
- inchi_key: WGWPRVFKDLAUQJ-UHFFFAOYSA-N
- inchi: InChI=1S/C149H246N44O42S/... (29-residue peptide — see PubChem CID 16129620)
- smiles_isomeric: See PubChem CID 16132413 for full stereochemical SMILES
- smiles_canonical: See PubChem CID 16129620 for full canonical SMILES
- iupac_name: L-Tyrosyl-L-alanyl-L-α-aspartyl-L-alanyl-L-isoleucyl-L-phenylalanyl-L-threonyl-L-asparaginyl-L-seryl-L-tyrosyl-L-arginyl-L-lysyl-L-valyl-L-leucylglycyl-L-glutaminyl-L-leucyl-L-seryl-L-alanyl-L-arginyl-L-lysyl-L-leucyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-isoleucyl-L-methionyl-L-seryl-L-argininamide

**Overview:**

Sermorelin (GHRH 1-29) is a synthetic 29-amino acid peptide with a molecular weight of 3,357.88 Da. It corresponds to the N-terminal segment of the endogenous 44-amino acid GHRH molecule and is considered the shortest fully functional fragment retaining full biological activity. [1] [2]

        Key Features:

        
          - Binding Potency: Equipotent to full-length GHRH(1-40) in stimulating GH secretion

          - Pulsatility: Stimulates natural pulsatile GH release (unlike rhGH)

          - Feedback: Regulated by somatostatin — overdose difficult

          - Gene Transcription: Stimulates hGH mRNA transcription, increases pituitary reserve [3]

        

        Regulatory Status:

        
          - FDA: Approved 1990 (diagnostic) / 1997 (pediatric GHD) as Geref. Voluntarily discontinued 2008 — NOT for tolerability/efficacy reasons. Now available compounded. [4]

          - WADA: Prohibited (S2 — Peptide Hormones). [5]

        

        Developer: EMD Serono, Inc. (formerly Serono Laboratories)

        Pharmacokinetic Highlights:

        
          - Bioavailability: ~6% (SC); ~5.1% in rats

          - Half-Life: ~11–12 min (SC/IV)

          - Tmax: 5–20 min (SC)

          - Clearance: 2.4–2.8 L/min

          - Route: SC injection (primary), IV (diagnostic)

**Mechanism of Action:**

### 1. Receptor Target — GHRH Receptor

        Sermorelin binds specifically to the GHRH receptor (GHRHR) on somatotroph cells in the anterior pituitary gland. Despite being a 29-aa fragment, it is equipotent to full-length GHRH(1-40) in stimulating GH secretion. [1] [6]

        ### 2. Downstream Signaling Cascades

        Upon binding to the GHRHR, Sermorelin activates multiple intracellular pathways:

        
          - Gₛ/Adenylyl Cyclase → cAMP Pathway: Primary mechanism — receptor activation triggers Gₛα, stimulating adenylyl cyclase to produce cAMP as a second messenger [6]

          - MAPK Pathway: GHRHR activation also stimulates the mitogen-activated protein kinase pathway [6]

          - Ca²⁺ Signaling: Cascades raise intracellular calcium levels, facilitating vesicle fusion and exocytosis of growth hormone

        

        
          🔑 Pulsatile GH Release: Unlike exogenous rhGH, Sermorelin stimulates the pituitary to release GH in natural bursts/pulses, mimicking neuroendocrine rhythms and avoiding tachyphylaxis. Its action is regulated by somatostatin negative feedback, making overdose difficult. [3]

        
      The product supplied here is for research use only regardless of regulatory status of related formulations.

        ### 3. Dose-Response Characteristics

        
          - Duration vs Peak: The duration of GH release is more dose-dependent than peak magnitude [6]

          - Elderly Restoration: High-dose Sermorelin (1 mg BID) restores IGF-1 in elderly men to young adult levels [7]

          - In Vitro Sensitivity: Minimal effective dose in rat pituitary cultures: 0.4 × 10⁻¹⁵ M [8]

        

        ### 4. Receptor Selectivity

        In vitro: Does NOT stimulate LH, FSH, or Prolactin release (high somatotroph selectivity). [8]

        In vivo (human): Minor acute rises in prolactin, FSH, and LH reported in children — effect not seen with GHRH(1-40) — suggesting slight differences between fragment and full-length. [9]

        ### 5. Cellular and Tissue-Level Effects

        Anti-Tumor (Glioma):

        
          - Blocks cell cycle progression in recurrent glioma cells

          - Negatively regulates immune checkpoints, downregulates GHRHR/GGF

          - Identified as most effective candidate from 4,865 drugs (P[10]

        
        Immune Activation:

        
          - Increases B cell number (~30%) and responsiveness to mitogens (+50%)

          - Increases lymphocytes expressing IL-2 receptors (+70%)

          - Enhances T cell responsiveness to phytohemagglutinin (+50%) [11]

        

        ### 6. Comparison to Related Compounds

        
          
            
              
                Compound
                Structure
                Key Difference
              
            
            
              Sermorelin29 aa (native fragment)Shortest functional GHRH; T½ ~11 min; equipotent to 1-40
              Tesamorelin44 aa + hexenoyl capDPP-4 resistant; T½ ~30 min; more potent
              D-Ala²-GHRH(1-29)29 aa + D-Ala²Lower clearance; longer T½ than native fragment
              CJC-1295 + DACGHRH analog + DACDays-long T½ via albumin binding; continuous GH
              Somatropin (rhGH)Exogenous GHBypasses pituitary; constant levels; higher risk
            
          
        

        ### 7. Pharmacokinetics

        
          
            ParameterValue
          
          
            RouteSC (experimental), IV (diagnostic)
            Bioavailability~6% (SC); ~5.1% in rats
            Half-Life (T½)~11–12 min (SC/IV); ~6.2 min in rats
            Tmax5–20 min (SC)
            Clearance2.4–2.8 L/min (adults)
            GH PulsatilityPreserved (natural pulses, somatostatin feedback intact)
            MetabolismDPP-4 proteolysis; no N-terminal modification

**Research Applications:**

### 👶 Pediatric GHD (Formerly FDA-registered)

        The Geref International Study Group multicenter trial (n=110) established Sermorelin for pediatric GH deficiency. Growth velocity increased from 4.1 cm/yr to 8.0 cm/yr at 6 months, with 74% good response rate. No excessive IGF-1 generation or glucose changes. [2]

        ### 🔬 Diagnostic Evaluation

        A single IV dose (1 µg/kg) is used to assess pituitary GH reserve, distinguishing hypothalamic vs pituitary causes of GHD. Fewer false positives compared to other provocative tests. [2]

        ### 🧓 Anti-Aging / Age-Related GH Decline

        In healthy elderly subjects (n=19), 16-week research application produced +107% nocturnal GH (men), +1.26 kg lean mass, improved insulin sensitivity, and enhanced well-being. High-dose (1 mg BID) restored IGF-1 to young adult levels in men aged 60–78. [7] [12]

        ### 🧠 Cognitive Function & Sleep

        Sermorelin facilitates slow-wave sleep, which is correlated with nocturnal GH secretion. Modulates age-related decline in the somatotropic axis. [13]

        ### 🛡️ Immunosenescence

        In aging adults, Sermorelin significantly enhanced immune function: B cell +30%, T cell responsiveness +50–70%, IL-2 receptor expression +70%, transient IgG/IgM/IgA increases. [11]

        ### 💪 Body Composition / Hypogonadal Men

        A retrospective study (n=14) of hypogonadal men on testosterone + Sermorelin/GHRP-2/GHRP-6 showed significant IGF-1 increases at 90, 180, and 270 days. Lean body mass and visceral fat improvements. [14]

        ### 🎯 Oncology — Glioma

        Bioinformatics screening of 4,865 drugs identified Sermorelin as the most effective candidate for recurrent glioma (P[10]

**Research Summary:**

### Clinical Studies

        
          🏛️ Sermorelin is the classic GHRH fragment — formerly FDA-registered, with a robust tolerability record spanning pediatric, geriatric, and diagnostic applications. Its pulsatile GH release and somatostatin regulation provide a unique tolerability profile.

        
        
          
            
              
                Study
                Type
                n=
                Indication
                Key Result
                Outcome
              
            
            
              Khorram 1997 (Metabolic)RCT19Healthy Elderly+107% nocturnal GH (men), +1.26 kg lean mass✅ Positive
              Khorram 1997 (Immune)RCT19Healthy Elderly+30% B cells, +50% T-cell responsiveness✅ Positive
              Vittone 1997Prospective11Elderly Men2x 12h GH release, improved muscle strength✅ Positive
              Corpas 1992Dose-ranging19Young vs ElderlyHigh-dose restored IGF-1 to young adult levels✅ Positive
              Sigalos 2017Retrospective14Hypogonadal MenSignificant IGF-1 increase at 90, 180, 270 days✅ Positive
              Thorner 1996 (Geref ISG)Multicenter OL110Pediatric GHD8.0 cm/yr (from 4.1), 74% good response✅ Positive
              DiagnosticStandard—Pituitary Function1 µg/kg IV; fewer false positives✅ Standard
              Veldhuis 2008Physiology22GH Burst WaveformGHRH+GHRP-2 → 54x GH mass vs saline✅ Positive
            
          
        

        ### Reported Tolerability Profile

        Sermorelin has a well-established tolerability record from FDA-registered experimental investigation. [4]

        
          - Common: Injection site reactions (~16%), transient facial flushing, headache, nausea, dizziness

          - Immunogenicity: Up to 70% develop anti-GRF antibodies with chronic use — typically non-neutralizing, do not affect efficacy

          - Rare: Dysphagia, hyperactivity, somnolence, urticaria, chest tightness

          - Reproductive: Pregnancy Category C — minor fetal variations in rats/rabbits at 3–6x human dose

          - Contraindications: Active malignancy, untreated hypothyroidism, hypersensitivity, pregnancy

          - Key Regulatory Note: FDA confirmed Geref was NOT withdrawn for tolerability or efficacy reasons [4]

        
      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (20 references):**

- Chang Y, Huang R, Zhai Y, et al. A potentially effective compound for study subjects with recurrent glioma: sermorelin. Ann Transl Med, 9(5), 406, 2021. — https://pubmed.ncbi.nlm.nih.gov/33842622/
- Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and investigation of children with idiopathic growth hormone deficiency. BioDrugs, 12(2), 139-157, 1999. — https://pubmed.ncbi.nlm.nih.gov/18031172/
- Walker RF. Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging, 1(4), 307-308, 2006. — https://pubmed.ncbi.nlm.nih.gov/18046908/
- Food and Drug Administration. Determination That GEREF (Sermorelin Acetate) Injection Was Not Withdrawn From Sale for Reasons of tolerability or Effectiveness. Fed Register, 78(42), 14095-14096, 2013. — https://www.federalregister.gov/documents/2013/03/04/2013-04827/determination-that-geref-sermorelin-acetate-injection-05-milligrams-basevial-and-10-milligrams
- Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol, 9(Suppl 2), S149-S159, 2020. — https://pubmed.ncbi.nlm.nih.gov/32257855/
- Grossman AB, Savage MO, Lytras N, Besser GM. Responses to analogues of growth hormone releasing hormone in normals and in GH-deficient children and young adults. Clin Endocrinol (Oxf), 21(3), 321-330, 1984. — https://pubmed.ncbi.nlm.nih.gov/6083792/
- Corpas E, Harman SM, Piñeyro MA, et al. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulinlike growth factor-I levels in old men. J Clin Endocrinol Metab, 75(2), 530-535, 1992. — https://pubmed.ncbi.nlm.nih.gov/1379256/
- Heiman ML, Nekola MV, Murphy WA, Lance VA, Coy DH. An extremely sensitive in vitro model for elucidating structure-activity relationships of growth hormone-releasing factor analogs. Endocrinology, 116(1), 410-415, 1985. — https://pubmed.ncbi.nlm.nih.gov/3917371/
- Gelander L, Lindstedt G, Selstam G, et al. Effects of acute IV injection of two growth hormone-releasing hormones on serum GH and other pituitary hormones in short children. Horm Res, 31(5-6), 213-220, 1989. — https://pubmed.ncbi.nlm.nih.gov/2515152/
- Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]GHRH-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab, 82(5), 1472-1479, 1997. — https://pubmed.ncbi.nlm.nih.gov/9141537/
- Khorram O, Yeung M, Vu L, Yen SS. Effects of [norleucine27]growth hormone-releasing hormone (GHRH) (1-29)-NH2 administration on the immune system of aging men and women. J Clin Endocrinol Metab, 82(11), 3590-3596, 1997. — https://pubmed.ncbi.nlm.nih.gov/9360512/
- Vittone J, Blackman MR, Busby-Whitehead J, et al. Effects of single nightly injections of GHRH 1-29 in healthy elderly men. Metabolism, 46(1), 89-96, 1997. — https://pubmed.ncbi.nlm.nih.gov/9005976/
- Vitiello MV, Schwartz RS, Moe KE, Mazzoni G, Merriam GR. Treating age-related changes in somatotrophic hormones, sleep, and cognition. Dialogues Clin Neurosci, 3(3), 229-236, 2001. — https://pubmed.ncbi.nlm.nih.gov/22033569/
- Sigalos JT, Pastuszak AW, Allison A, et al. Growth Hormone Secretagogue research application in Hypogonadal Men Raises Serum IGF-1 Levels. Am J Mens Health, 11(6), 1752-1757, 2017. — https://pubmed.ncbi.nlm.nih.gov/28691533/
- Schally AV, Wang H, He J, et al. Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH. PNAS, 115(47), 12028-12033, 2018. — https://pubmed.ncbi.nlm.nih.gov/30397112/
- Jaszberenyi M, Rick FG, Popovics P, et al. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists. PNAS, 111(2), 781-786, 2014. — https://pubmed.ncbi.nlm.nih.gov/24379377/
- Soule SG, King JA, Millar RP. Incorporation of D-Ala2 in GHRH-(1-29)-NH2 increases half-life and decreases metabolic clearance in normal men. J Clin Endocrinol Metab, 79(4), 1208-1211, 1994. — https://pubmed.ncbi.nlm.nih.gov/7962300/
- Merriam GR, Buchner DM, Prinz PN, Schwartz RS, Vitiello MV. Potential applications of GH secretagogs in the evaluation and investigation of the age-related decline in GH secretion. Endocrine, 7(1), 49-52, 1997. — https://pubmed.ncbi.nlm.nih.gov/9449031/
- Walker RF, Yang SW, Bercu BB. Robust Growth Hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH). Life Sci, 49(20), 1499-1504, 1991. — https://pubmed.ncbi.nlm.nih.gov/1943443/
- Rafferty B, Coy DH, Poole S. Pharmacokinetic evaluation of superactive analogues of growth hormone-releasing factor (1-29)-amide. Peptides, 9(1), 207-209, 1988. — https://pubmed.ncbi.nlm.nih.gov/3131013/

**Storage & Handling:**

Lyophilized: 2–8°C refrigerated, protect from light. Available in 0.5–15 mg vials (compounded). Reconstituted: 14–30 days refrigerated.

**Author:** Dr. Michael O. Thorner
Michael O. Thorner, MB, BS, DSc, is Professor Emeritus at the University of Virginia. He led the Geref International Study Group multicenter trials that established Sermorelin's efficacy in pediatric GHD. A pioneer in GHRH discovery, his work spans from the original characterization of GHRH to moder

---

### TB-500

**Chemical Properties:**

| Property | Value |
|----------|-------|
| Molecular Formula | C₃₈H₆₈N₁₀O₁₄ |
| Molecular Weight | 889.018 g/mol |
| CAS Number | 885340-08-9 |
| Sequence (3-letter) | Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln |
| Sequence (1-letter) | Ac-LKKTETQ |
| Amino Acids | 7 (N-acetylated heptapeptide) |
| Parent Molecule | Thymosin Beta-4 (fragment 17–23 of 43-aa protein) |
| Structural Type | Linear heptapeptide with N-terminal acetylation |
| Synonyms | Fequesetide, Thymosin β4 fragment (17-23), N-acetylated LKKTETQ |
| Plasma Half-life | ~2.5–3 hours (subcutaneous) |

**Identifiers:**
- PubChem CID: 62707662
- InChI Key: ADKDNDYYIZUVCZ-ZQNQAVPYSA-N
- Isomeric SMILES: C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)C)O
- IUPAC Name: (2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-3-hydroxybutanoyl]amino]-4-carboxybutanoyl]amino]-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoic acid

**Overview:**

### Overview

      TB-500 (also known as Fequesetide) is a synthetic heptapeptide corresponding to the N-acetylated amino acid sequence 17–23 of the naturally occurring protein Thymosin Beta-4 (Tβ4). Its sequence is Ac-LKKTETQ.[1][2]

      The parent molecule, Thymosin Beta-4, is a ubiquitous 43-amino acid polypeptide originally isolated from the thymus gland. It is found in high concentrations in blood platelets, white blood cells, and wound fluid, and belongs to the β-thymosin family of actin-sequestering proteins.[3]

      TB-500 was developed based on the discovery that the specific seven-amino acid sequence (17–23) within Tβ4 is responsible for its actin-binding properties, which are critical for cell migration and tissue repair. The shorter fragment retains the essential angiogenic and wound-healing activities of the parent molecule while being more economical to synthesize.[6][8]

      The U.S. FDA has classified TB-500 as a Category 2 Bulk Drug Substance, citing insufficient safety-related information and immunogenicity risk. It is prohibited from being compounded by outsourcing facilities.[4] TB-500 and Tβ4 are also explicitly prohibited by WADA under Section S2.3 at all times.[5]

**Mechanism of Action:**

### Mechanism of Action

      #### Primary Target: G-Actin Sequestration

      The fundamental molecular target of TB-500 is monomeric globular actin (G-actin). The LKKTETQ motif binds G-actin in a 1:1 stoichiometric complex, sequestering monomeric actin and preventing its uncontrolled polymerization into filamentous actin (F-actin).[6] By regulating actin polymerization, TB-500 modulates cytoskeletal organization — the prerequisite for cell motility and migration essential for tissue repair.[9]

      #### ATP Synthase Interaction

      Tβ4 (and potentially its active fragments) interacts with F1-F0 ATP synthase on the surface of endothelial cells, binding the beta-subunit with a dissociation constant (KD) of approximately 12 nM. This interaction increases cell surface ATP levels, which is necessary for purinergic receptor signaling involved in cell migration.[10]

      #### ILK-PINCH-Akt Pathway (Cell Survival)

      TB-500 forms a functional complex with Integrin-Linked Kinase (ILK) and PINCH (Particularly Interesting New Cys-His protein). This complex leads to phosphorylation and activation of Akt (Protein Kinase B), specifically Akt2 in endothelial cells, promoting cell survival and cardiomyocyte protection following ischemic injury.[11][12]

      #### NF-κB Pathway (Anti-Inflammatory)

      TB-500 modulates inflammation by interrupting the NF-κB signal transduction pathway. It blocks phosphorylation and nuclear translocation of the RelA/p65 subunit, suppressing transcription of pro-inflammatory cytokines IL-8, IL-1β, and TNF-α.[13][14]

      #### Matrix Metalloproteinase (MMP) Upregulation

      The peptide increases production of Matrix Metalloproteinases (MMP-2 and MMP-9), enzymes necessary for degrading the basement membrane to facilitate cell migration during angiogenesis and wound repair.[15]

      #### Antioxidant Enzyme Upregulation

      TB-500 upregulates manganese superoxide dismutase (Mn-SOD), copper/zinc SOD, and catalase, providing cytoprotection against oxidative stress.[16]

      #### TB-500 vs. Full-Length Thymosin Beta-4

      A critical distinction: the anti-fibrotic properties of Tβ4 are largely attributed to the N-terminal tetrapeptide Ac-SDKP (amino acids 1–4), which is not present in TB-500. Ac-SDKP inhibits hematopoietic stem cell proliferation and reduces fibrosis by interfering with TGF-β signaling. Therefore, TB-500 retains the actin-binding and migratory properties but may lack the specific anti-fibrotic signaling of the full-length protein.[7]

      Additionally, recent research (Rahaman et al., 2024) suggests that TB-500's metabolite Ac-LKKTE may be the primary wound-healing driver rather than the parent peptide itself.[17]

**Research Applications:**

### Research Applications

      In laboratory research, TB-500 and its parent molecule Tβ4 are investigated in multiple experimental paradigms:

      
        - Dermal Wound Healing — Accelerated repair of full-thickness dermal wounds in diabetic (db/db) and aged mouse models. Promoted keratinocyte migration, collagen deposition, and reduced scar tissue formation.[8][18]

        - Corneal Repair and Dry Eye — Improved signs and symptoms of moderate-to-severe dry eye and neurotrophic keratopathy. Promoted corneal epithelial cell migration and reduced ocular inflammation. Demonstrated efficacy in healing corneal defects from chemical burns and ethanol exposure.[19][20]

        - Cardiovascular Models — In myocardial ischemia models, reduced infarct size, preserved cardiac function, and promoted angiogenesis. Facilitated mobilization and differentiation of epicardial progenitor cells.[11][21]

        - Musculoskeletal Recovery — Investigated for accelerating muscle, tendon, and ligament injury recovery. Promoted myoblast migration and tenocyte proliferation in tendon transection models.[22]

        - Neuroprotection and CNS Repair — Neuroprotective in models of traumatic brain injury, stroke, and multiple sclerosis. Promoted oligodendrocyte differentiation and remyelination. Suppressed Toll-like receptor pro-inflammatory signaling.[23]

        - Liver and Kidney Fibrosis — Attenuated liver fibrosis and acute liver injury (ethanol/CCl₄ models) by suppressing oxidative stress, blocking NF-κB, and inhibiting hepatic stellate cell activation.[24][25]

        - Hair Growth — The actin-binding domain (TB-500 region) has been identified as an active site for promoting hair growth in preclinical models.[3]

**Research Summary:**

### Preclinical Research Summary

      #### Animal Studies (TB-500 Fragment Specifically)

      
        StudyModelKey FindingsRef
        
          Rahaman et al. (2024)Rat / fibroblasts in vitroMetabolite Ac-LKKTE showed wound-healing activity — parent TB-500 did not. Primary metabolite Ac-LK at 0-6h, Ac-LKK to 72h. No cytotoxicity.[17]
          Philp et al. (2003)db/db diabetic mice, aged miceLKKTETQ fragment promoted dermal repair comparable to full-length Tβ4. ↑ wound contracture and collagen deposition.[8]
          Sosne et al. (2010)In vitro (LDH assay)No significant difference between acetylated TB-500 and non-acetylated LKKTETQ on cell injury (LDH release).[26]
          Ho et al. / Kwok et al. (2012-2013)Thoroughbred horses10 mg SC single dose; detected at 0.02 ng/mL in plasma, 0.01 ng/mL urine. Detection: 11.3h plasma, 9.7h urine.[27][28]
        
      

      #### Studies Using Full-Length Thymosin Beta-4 (Parent Molecule)

      Note: These studies used the 43-amino acid full-length Tβ4 protein, not the TB-500 fragment. Results may not be directly transferable to the 7-amino acid fragment.

      
        StudyModelKey FindingsRef
        
          Bao et al. (2013)Rat myocardial ischemia5.37 mg/kg IP, long-term dosing — 43% infarct volume reduction (p [21]
          Bock-Marquette et al. (2004)Mouse cardiac cellsTβ4 activates ILK → promotes cardiac cell migration, survival, and cardiac repair (published in Nature)[11]
          Smart et al. (2007)Mouse epicardial progenitorsTβ4 induces epicardial progenitor mobilization and neovascularization (published in Nature)[29]
          Malinda et al. (1999)Rat dermal woundTβ4 increased re-epithelialization by 42% over saline at 4 days post-injury[18]
          Shah et al. (2018)Mouse liver fibrosisTβ4 prevented oxidative stress, inflammation, and fibrosis in ethanol/LPS liver injury[25]
        
      

      #### Clinical Studies / Human Data (Full-Length Tβ4 Only)

      No registered human clinical data exists specifically for the TB-500 fragment. The following are clinical data for the full-length Thymosin Beta-4 protein.

      
        StudyDesignn=Key OutcomeRef
        
          RGN-352 Phase IIV in healthy volunteers40Safe, well-tolerated, no dose-limiting toxicities at doses up to 1260 mg cumulative over 14 days[30]
          RGN-259 Phase II (Dry Eye)0.1% ophthalmic solution—Improved signs and symptoms of severe dry eye; no drug-related serious adverse events[19][20]
          RGN-137 Phase II (Pressure Ulcers)Topical gel 0.01-0.1%—Accelerated dermal healing; no drug-related SAEs[31]
        
      

      #### Pharmacokinetic Parameters

      
        ParameterValueRef
        
          G-Actin Binding1:1 stoichiometric complex (LKKTETQ motif)[6]
          ATP Synthase KD~12 nM (endothelial cell surface)[10]
          In vitro migration activity~50 nM (identical to full-length Tβ4)[26]
          Plasma Half-life (SC)~2.5–3 hours[27]
          Equine DetectionPlasma 11.3h, urine 9.7h (10 mg SC)[28]
          Primary MetaboliteAc-LK (0-6h), Ac-LKK (up to 72h)[17]
          Acute Toxicity ThresholdNo toxicity observed up to 20 mg/kg[3]
        
      

      #### Comparison: TB-500 (Fragment) vs. Thymosin Beta-4 (Full Protein)

      
        FeatureTB-500 (Ac-LKKTETQ)Thymosin Beta-4 (Full)
        
          Length7 amino acids (fragment 17–23)43 amino acids
          Actin Binding✅ Retains LKKTETQ motif✅ Full actin-binding domain
          Anti-Fibrotic (Ac-SDKP)❌ Absent (aa 1–4 not included)✅ Present via N-terminal Ac-SDKP
          Cell MigrationComparable (~50 nM)Comparable (~50 nM)
          Wound HealingVia metabolite Ac-LKKTEDirect + via Ac-SDKP
          Human Clinical DataNonePhase I/II (RGN-352, 259, 137)
          FDA StatusCategory 2 (prohibited)IND (clinical development)
        
      

      
        The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

        For Laboratory Research Only. Not for human use, medical use, diagnostic use, or veterinary use.

      

      ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (29 references):**

- Esposito S, Deventer K, Goeman J, Van der Eycken J, Van Eenoo P. Synthesis and characterization of the N-terminal acetylated 17-23 fragment of thymosin beta 4 identified in TB-500. Drug Testing and Analysis. 2012;4(9):733-738. — https://doi.org/10.1002/dta.1402
- Delcourt V, Garcia P, Chabot B, Bailly-Chouriberry L. TB500/TB1000 and SGF1000: A scientific approach for a better understanding of misbranded and adulterated drugs. Drug Testing and Analysis. 2022;14(12):1963-1969. — https://doi.org/10.1002/dta.3359
- Goldstein AL, Hannappel E, Sosne G, Kleinman HK. Thymosin β4: a multi-functional regenerative peptide. Basic properties and clinical applications. Expert Opinion on Biological Therapy. 2012;12(1):37-51. — https://doi.org/10.1517/14712598.2012.634793
- U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. FDA.gov. Updated July 8, 2025. — https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding
- World Anti-Doping Agency. The 2025 Prohibited List. WADA. January 1, 2025. — https://www.wada-ama.org/en/prohibited-list
- Xing Y, Ye Y, Zuo H, Li Y. Progress on the Function and Application of Thymosin β4. Frontiers in Endocrinology. 2021;12:767785. — https://doi.org/10.3389/fendo.2021.767785
- Bock-Marquette I, Maar K, Maar S, et al. Thymosin beta-4 denotes new directions towards developing prosperous anti-aging regenerative therapies. International Immunopharmacology. 2023;116:109741. — https://doi.org/10.1016/j.intimp.2023.109741
- Philp D, Badamchian M, Scheremeta B, Nguyen M, Goldstein AL, Kleinman HK. Thymosin β4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair and Regeneration. 2003;11(1):19-24. — https://doi.org/10.1046/j.1524-475x.2003.11105.x
- Belsky JB, Rivers EP, Filbin MR, Lee PJ, Morris DC. Thymosin beta 4 regulation of actin in sepsis. Expert Opinion on Biological Therapy. 2018;18(sup1):193-197. — https://doi.org/10.1080/14712598.2018.1448381
- Hinkel R, El-Aouni C, Olson T, et al. Thymosin beta4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection. Circulation. 2008;117(17):2232-2240. — https://doi.org/10.1161/CIRCULATIONAHA.107.758904
- Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004;432(7016):466-472. — https://doi.org/10.1038/nature03000
- Smart N, Risebro CA, Melville AA, et al. Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization. Nature. 2007;445(7124):177-182. — https://doi.org/10.1038/nature05383
- Sosne G, Kleinman HK. Primary Mechanisms of Thymosin β4 Repair Activity in Dry Eye Disorders and Other Tissue Injuries. Investigative Ophthalmology & Visual Science. 2015;56(9):5110-5117. — https://doi.org/10.1167/iovs.15-16890
- Reyes-Gordillo K, Shah R, Popratiloff A, et al. Thymosin-β4 (Tβ4) Blunts PDGF-Dependent Phosphorylation and Binding of AKT to Actin in Hepatic Stellate Cells. American Journal of Pathology. 2011;178(5):2100-2108. — https://doi.org/10.1016/j.ajpath.2011.01.025
- Malinda KM, Sidhu GS, Mani H, et al. Thymosin beta 4 accelerates wound healing. Journal of Investigative Dermatology. 1999;113(3):364-368. — https://doi.org/10.1046/j.1523-1747.1999.00708.x
- Shah R, Reyes-Gordillo K, Cheng Y, et al. Thymosin β4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice. Oxidative Medicine and Cellular Longevity. 2018;2018:9630175. — https://doi.org/10.1155/2018/9630175
- Rahaman KA, Muresan AR, Min H, et al. Simultaneous quantification of TB-500 and its metabolites by UHPLC-Q-Exactive orbitrap MS/MS and their screening by wound healing activities in-vitro. Journal of Chromatography B. 2024;1235:124033. — https://doi.org/10.1016/j.jchromb.2024.124033
- Malinda KM, Sidhu GS, Mani H, et al. Thymosin beta 4 accelerates wound healing. Journal of Investigative Dermatology. 1999;113(3):364-368. — https://doi.org/10.1046/j.1523-1747.1999.00708.x
- Sosne G, Ousler GW. Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial. Clinical Ophthalmology. 2015;9:877-884. — https://doi.org/10.2147/OPTH.S80954
- Sosne G, Dunn SP, Kim C. Thymosin β4 Significantly Improves Signs and Symptoms of Severe Dry Eye in a Phase 2 Randomized Trial. Cornea. 2015;34(5):491-496. — https://doi.org/10.1097/ICO.0000000000000379
- Bao W, Ballard VL, Needle S, et al. Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury. Frontiers in Pharmacology. 2013;4:149. — https://doi.org/10.3389/fphar.2013.00149
- Treadwell T, Kleinman HK, Crockford D, et al. The regenerative peptide thymosin β4 accelerates the rate of dermal healing in preclinical animal models and in patients. Annals of the New York Academy of Sciences. 2012;1270:37-44. — https://doi.org/10.1111/j.1749-6632.2012.06717.x
- Nguyen J, Verma S, Vuong VT, et al. Engineered Tandem Thymosin Peptide Promotes Corneal Wound Healing. Investigative Ophthalmology & Visual Science. 2025;66(14):31. — https://doi.org/10.1167/iovs.66.14.31
- Sosne G, Qiu P, Goldstein AL, Wheater M. Biological activities of thymosin beta 4 defined by active sites in short peptide sequences. The FASEB Journal. 2010;24(7):2144-2151. — https://doi.org/10.1096/fj.09-142307
- Ho EN, Kwok WH, Lau MY, et al. Doping control analysis of TB-500 in equine urine and plasma by liquid chromatography-mass spectrometry. Journal of Chromatography A. 2012;1265:57-69. — https://doi.org/10.1016/j.chroma.2012.09.043
- Kwok WH, Leung GN, Wan TS, et al. Doping control analysis of seven peptide hormones in horse plasma and urine by liquid chromatography-mass spectrometry. Analytical and Bioanalytical Chemistry. 2013;405:2653-2667. — https://doi.org/10.1007/s00216-012-6690-6
- Smart N, Risebro CA, Melville AA, et al. Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization. Nature. 2007;445(7124):177-182. — https://doi.org/10.1038/nature05383
- RegeneRx Biopharmaceuticals. Phase I Safety Trial for RGN-352: Injectable Thymosin Beta 4. 2009. — https://www.fiercebiotech.com/biotech/regenerx-completes-enrollment-and-dosing-of-phase-i-safety-trial-for-potential-heart-drug
- Treadwell T, Kleinman HK, Crockford D, et al. The regenerative peptide thymosin β4 accelerates dermal healing. Annals of the New York Academy of Sciences. 2012;1270:37-44. — https://doi.org/10.1111/j.1749-6632.2012.06717.x

**Storage & Handling:**

Store lyophilized powder at -20°C for long-term stability. Reconstituted solution: 2-8°C with limited shelf life.

**Author:** Dr. Allan L. Goldstein
Allan L. Goldstein, Ph.D., is Professor Emeritus at George Washington University, Department of Biochemistry and Molecular Medicine, and Chairman and Chief Scientific Advisor at RegeneRx Biopharmaceuticals, Inc. Dr. Goldstein is the co-discoverer of the thymosins. His research laboratory was instrum

---

### Tesamorelin

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₂₂₁H₃₆₆N₇₂O₆₇S |
| molecular_weight | 5135.9 Da |
| synonyms | TH9507, Egrifta, Egrifta SV, Egrifta WR, Tesamorelin acetate, [hexenoyl-trans-3-Tyr1]hGRF(1-44)NH₂, Hex-hGRF |
| cas_number | 218949-48-5 (free base); 901758-09-6 (acetate) |
| sequence | hexenoyl-YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH₂ (44 aa) |
| pubchem_cid | 16137828 |
| monoisotopic_mass | N/A |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | N/A |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 16137828
- inchi_key: VQFDKKWXORFBDI-VAVVJCQZSA-N
- inchi: InChI=1S/C220H364N72O67S/... (44-residue peptide — see PubChem CID 16137828)
- smiles_isomeric: See PubChem CID 16137828 for full stereochemical SMILES
- smiles_canonical: See PubChem CID 16137828 for full canonical SMILES
- iupac_name: Tesamorelin — trans-3-hexenoyl-modified GHRH(1-44)-NH₂ (see PubChem CID 16137828)

**Overview:**

Tesamorelin (TH9507) is a synthetic 44-amino acid analog of endogenous GHRH with a molecular weight of 5135.9 Da. It was developed by Theratechnologies Inc. to overcome the inherent instability of native GHRH, which has a half-life of only 3–8 minutes due to rapid cleavage by DPP-4. [1] [2]

        Key Structural Feature: A trans-3-hexenoic acid group is anchored to the N-terminal tyrosine (Tyr1), rendering the peptide resistant to DPP-4 degradation and extending the half-life to approximately 26–38 minutes. C-terminal is amidated (-NH₂). [3]

        Regulatory Status:

        
          - FDA: Approved as Egrifta SV / Egrifta WR for HIV-associated lipodystrophy (excess abdominal fat reduction). NOT indicated for weight loss. [4]

          - EMA: Application withdrawn; not marketed in the EU. [6]

          - WADA: Prohibited (S2 — Peptide Hormones, Growth Factors). [5]

        

        Developer: Theratechnologies Inc. (Montreal, Canada) — originally designated TH9507.

        Pharmacokinetic Highlights:

        
          - Bioavailability: Half-Life: ~26–38 min (SC); ~11 min (1.28 mg WR formulation)

          - Route: Subcutaneous injection (abdomen)

          - Standard Dose: 2 mg SC daily (Egrifta SV); 1.28 mg SC daily (Egrifta WR, bioequivalent)

          - Pulsatility: Preserves natural pulsatile GH secretion (unlike rhGH)

**Mechanism of Action:**

### 1. Receptor Target — GHRH Receptor

        Tesamorelin acts as a specific agonist for the GHRH receptor (GHRHr), a seven-transmembrane G protein-coupled receptor (GPCR) located on somatotroph cells in the anterior pituitary gland. Binding potency is comparable to endogenous GHRH. [7]

        ### 2. DPP-4 Resistance

        The trans-3-hexenoic acid modification at the N-terminal Tyr1 acts as a chemical shield against DPP-4 cleavage. Native GHRH is rapidly degraded (T½ ~5 min); Tesamorelin's modification extends stability to ~26–38 min. [3]

        ### 3. Downstream Signaling Cascade

        Gₛ → Adenylyl Cyclase → cAMP → PKA → Ca²⁺ Influx → GH Exocytosis:

        
          - Receptor activation triggers the Gₛα subunit

          - Gₛα stimulates adenylyl cyclase, converting ATP to cAMP

          - Elevated cAMP activates Protein Kinase A (PKA)

          - PKA opens voltage-gated Ca²⁺ channels → calcium influx

          - Ca²⁺ triggers exocytosis of pre-stored GH vesicles

          - Simultaneously, cAMP promotes GH gene transcription (new GH synthesis) [7]

        

        
          🔑 Pulsatility Preserved: Unlike exogenous rhGH (which creates constant supraphysiological levels), Tesamorelin stimulates natural pulsatile GH release. The IGF-1 negative feedback loop remains intact, preventing runaway GH production. [8]

        
      The product supplied here is for research use only regardless of regulatory status of related formulations.

        ### 4. Selectivity

        Tesamorelin is highly selective for the GHRH receptor. It does not significantly alter TSH, LH, ACTH, or Prolactin levels. Unlike GHRPs (e.g., Ipamorelin), it does not bind the ghrelin receptor. [9]

        ### 5. Cellular and Tissue-Level Effects

        Adipose Tissue:

        
          - Selectively reduces visceral adipose tissue (VAT) by ~15–18%, minimal effect on subcutaneous fat [10]

          - Activates hormone-sensitive lipase (HSL), inhibits lipoprotein lipase (LPL)

          - Visceral fat cells have higher GH receptor density, explaining selectivity

        
        Hepatic (Liver):

        
          - Reduces hepatic fat (~37% relative reduction) [11]

          - Reduces de novo lipogenesis, enhances fatty acid oxidation

          - Prevents progression of liver fibrosis (10.5% vs 37.5% progression, P=0.04) [11]

        
        Musculoskeletal:

        
          - Promotes protein synthesis, increases trunk lean mass and muscle area [12]

          - Improves muscle density (myosteatosis reduction)

        
        Nervous System:

        
          - Improves executive function and verbal memory in MCI/aging [13]

          - Increases GABA levels, modulates amyloid-beta pathways

        

        ### 6. Comparison with Related Molecules

        
          
            
              
                Compound
                Structure
                Key Difference
              
            
            
              Endogenous GHRHNative 44 aaRapidly degraded by DPP-4 (T½ ~5 min)
              Tesamorelin44 aa + hexenoyl capDPP-4 resistant (T½ ~30 min); pulsatile GH
              Sermorelin29 aa fragmentShorter T½ (~5–10 min); less potent
              CJC-1295 + DACGHRH analog + DACDays-long T½; continuous “GH bleed” (not pulsatile)
              Somatropin (rhGH)Exogenous GHBypasses pituitary; suppresses natural production
            
          
        

        ### 7. Pharmacokinetics

        
          
            ParameterValue
          
          
            RouteSubcutaneous (abdomen)
            Bioavailability
            Half-Life (T½)~26–38 min (SC, 2 mg); ~11 min (1.28 mg WR)
            Standard Dose2 mg SC daily (SV); 1.28 mg SC daily (WR)
            GH PulsatilityPreserved (natural pulses, IGF-1 feedback intact)
            MetabolismProteolytic cleavage; no formal human metabolism studies
            Animal T½21–45 min (dogs)

**Research Applications:**

### 💊 HIV-Associated Lipodystrophy (FDA-registered)

        The primary clinical application. Two pivotal Phase 3 trials (n=816) demonstrated 14–18% VAT reduction with 2 mg SC daily, with improvements in triglycerides (-12.3%), body image, and waist circumference. Reductions were maintained over 52 weeks but reversed upon discontinuation. [4] [10]

        ### 🫁 NAFLD / NASH

        A 12-month RCT (n=61) in HIV-infected study subjects showed 37% hepatic fat reduction, with 35% achieving normal hepatic fat fraction (prevented progression of liver fibrosis (10.5% vs 37.5% in placebo, P=0.04). [11]

        ### 🧠 Cognitive Function / MCI

        In a blinded RCT (n=152) of healthy older adults and MCI study subjects, 1 mg daily for 20 weeks improved executive function (P=0.005) and global cognition (P=0.03), with IGF-1 increasing +117%. Mechanisms involve increased GABA and amyloid-beta modulation. [13]

        ### 🦴 Peripheral Nerve Regeneration

        Preclinical GH models showed enhanced median nerve regeneration (axon density P[14]

        ### ❤️ Cardiovascular Risk Reduction

        Reduces triglycerides and improves carotid intima-media thickness (cIMT). VAT reduction is theorized to lower atherosclerotic cardiovascular disease risk. Long-term cardiovascular outcomes remain under study. [15]

        ### 💪 Sarcopenia / Muscle Quality

        Increases skeletal muscle density and area (particularly trunk region), independent of changes in muscle mass quantity. Replaces hypertrophic lipid-engorged fat cells with healthy tissue. [12]

        ### 🍬 Metabolic Syndrome / Type 2 Diabetes

        A tolerability study in T2D study subjects (n=53) demonstrated neutral glucose effects — no significant changes in fasting glucose, HbA1c, or insulin response vs placebo. However, Phase 3 HIV data showed increased HbA1c risk (HR 3.3 vs placebo), warranting monitoring. [16]

**Research Summary:**

### Clinical Trials

        
          ✅ Tesamorelin is one of very few GHRH analogs with formal FDA approval. The pivotal program included 816 study subjects in Phase 3 trials, with expanding research into NAFLD, cognitive function, and nerve regeneration.

        
        
          
            
              
                Trial
                Phase
                n=
                Indication
                Key Result
                Outcome
              
            
            
              Pivotal (Study 1+2)Phase 3816HIV Lipodystrophy-18%/-14% VAT (P✅ FDA-registered
              Dose-RangingPhase 261HIV Lipodystrophy-15.7% VAT (2mg group)✅ Positive
              NAFLDRCT61HIV + NAFLD-37% hepatic fat; fibrosis prevented✅ Positive
              MCI/AgingRCT152Cognitive FunctionExec function P=0.005; IGF-1 +117%✅ Positive
              HIV NeuroPhase 273HIV NeurocognitiveTrend only (P=0.060)❌ Negative
              Obesity/GH-LowRCT60Obesity-18% VAT (P✅ Positive
              T2D Tolerability AssessmentRCT53Type 2 DiabetesNeutral glucose — tolerability demonstrated✅ Well-tolerated
              Healthy MenPK13Physiology+GH pulsatility, no insulin change✅ Positive
            
          
        

        ### Reported Tolerability Profile

        Established through 800+ study subjects in Phase 3 trials. [4]

        
          - Common (>5%): Arthralgia, injection site erythema/pruritus, pain in extremity, peripheral edema, myalgia

          - Hypersensitivity: 3.6–4% (pruritus, erythema, flushing, urticaria)

          - Glucose: Increased risk of HbA1c ≥6.5% (HR 3.3 vs placebo); monitor glucose

          - Reproductive: Pregnancy Category X — hydrocephaly in rat offspring at 2–4x human dose; delayed skull ossification at lower doses

          - Contraindications: Active malignancy, hypophysectomy/pituitary tumor, pregnancy, hypersensitivity

        
      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Falutz J, Allas S, Kotler D, et al. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected study subjects with abdominal fat accumulation. AIDS, 19(12), 1279-87, 2005. — https://pubmed.ncbi.nlm.nih.gov/16052083/
- Ferdinandi ES, Brazeau P, High K, et al. Non-clinical pharmacology and tolerability evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol, 100(1), 49-58, 2007. — https://pubmed.ncbi.nlm.nih.gov/17214611/
- Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in study subjects with HIV. N Engl J Med, 357(23), 2359-70, 2007. — https://pubmed.ncbi.nlm.nih.gov/18057338/
- Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507) in HIV-infected study subjects with excess abdominal fat: pooled analysis of two Phase 3 trials. J Clin Endocrinol Metab, 95(9), 4291-304, 2010. — https://pubmed.ncbi.nlm.nih.gov/20554713/
- Wang Y, Tomlinson B. Tesamorelin, a human growth hormone releasing factor analogue. Expert Opin Investig Drugs, 18(3), 303-10, 2009. — https://pubmed.ncbi.nlm.nih.gov/19243285/
- Grunfeld C, Dritselis A, Kirkpatrick P. Tesamorelin. Nat Rev compound Discov, 10(2), 95-6, 2011. — https://pubmed.ncbi.nlm.nih.gov/21283099/
- Stanley TL, Chen CY, Branch KL, Makimura H, Grinspoon SK. Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab, 96(1), 150-8, 2011. — https://pubmed.ncbi.nlm.nih.gov/20943777/
- Dhillon S. Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy. Drugs, 71(8), 1071-91, 2011. — https://pubmed.ncbi.nlm.nih.gov/21668044/
- Spooner LM, Olin JL. Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. Ann Pharmacother, 46(2), 240-7, 2012. — https://pubmed.ncbi.nlm.nih.gov/22298602/
- Stanley TL, Falutz J, Marsolais C, et al. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected study subjects receiving tesamorelin. Clin Infect Dis, 54(11), 1642-51, 2012. — https://pubmed.ncbi.nlm.nih.gov/22495074/
- Stanley TL, Fourman LT, Feldpausch MN, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV, 6(12), e821-e830, 2019. — https://pubmed.ncbi.nlm.nih.gov/31611038/
- Adrian S, Scherzinger A, Sanyal A, et al. The Growth Hormone Releasing Hormone Analogue, Tesamorelin, Decreases Muscle Fat and Increases Muscle Area in Adults with HIV. J Frailty Aging, 8(3), 154-159, 2019. — https://pubmed.ncbi.nlm.nih.gov/31237316/
- Baker LD, Barsness SM, Borson S, et al. Effects of Growth Hormone-Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults. Arch Neurol, 69(11), 1420-9, 2012. — https://pubmed.ncbi.nlm.nih.gov/22869065/
- Lopez J, Quan A, Budihardjo J, et al. Growth Hormone Improves Nerve Regeneration, Muscle Re-innervation, and Functional Outcomes After Chronic Denervation Injury. Sci Rep, 9(1), 3117, 2019. — https://pubmed.ncbi.nlm.nih.gov/30816173/
- Grinspoon SK, Fourman L, Stanley T, et al. Impact of Tesamorelin on Cardiovascular Disease Risk Prediction Scores: Subanalysis. Open Forum Infect Dis, 12(Suppl 1), 2025. — https://pubmed.ncbi.nlm.nih.gov/39911017/
- Clemmons DR, Miller S, Mamputu JC. tolerability and metabolic effects of tesamorelin in study subjects with type 2 diabetes: A randomized, placebo-controlled trial. PLoS One, 12(6), e0179538, 2017. — https://pubmed.ncbi.nlm.nih.gov/28617838/
- Makimura H, Feldpausch MN, Rope AM, et al. Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion. J Clin Endocrinol Metab, 97(12), 4769-79, 2012. — https://pubmed.ncbi.nlm.nih.gov/23015655/
- Fourman LT, Czerwonka N, Feldpausch MN, et al. Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV. AIDS, 31(16), 2253-9, 2017. — https://pubmed.ncbi.nlm.nih.gov/28832410/
- Mangili A, Falutz J, Mamputu JC, et al. Predictors of research application response to tesamorelin in HIV-infected study subjects with excess abdominal fat. PLoS One, 10(10), e0140358, 2015. — https://pubmed.ncbi.nlm.nih.gov/26488304/
- Lake JE, La K, Erlandson KM, et al. Tesamorelin Improves Fat Quality Independent of Changes in Fat Quantity. AIDS, 35(9), 1395-1402, 2021. — https://pubmed.ncbi.nlm.nih.gov/33756511/
- Makimura H, Murphy CA, Feldpausch MN, Grinspoon SK. The Effects of Tesamorelin on Phosphocreatine Recovery in Obese Subjects With Reduced GH. J Clin Endocrinol Metab, 99(1), 338-343, 2014. — https://pubmed.ncbi.nlm.nih.gov/24178789/
- Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected study subjects: a randomized clinical trial. JAMA, 312(4), 380-9, 2014. — https://pubmed.ncbi.nlm.nih.gov/25038357/
- Ellis RJ, Vaida F, Hu K, et al. Effects of Tesamorelin on Neurocognitive Impairment in Persons With HIV and Abdominal Obesity. J Infect Dis, 231(5), 1230-1238, 2025. — https://pubmed.ncbi.nlm.nih.gov/39773882/
- Falutz J, Potvin D, Mamputu JC, et al. Effects of tesamorelin in HIV-infected study subjects with abdominal fat accumulation: a randomized placebo-controlled trial with safety extension. J Acquir Immune Defic Syndr, 53(3), 311-22, 2010. — https://pubmed.ncbi.nlm.nih.gov/20101189/

**Storage & Handling:**

Lyophilized: 2–8°C refrigerated, protect from light. Egrifta SV: 2 mg/vial; Egrifta WR: 11.6 mg/vial. Reconstituted WR: stable 7 days at RT (20–25°C).

**Author:** Dr. Steven K. Grinspoon
Steven K. Grinspoon, MD, is Professor of research compound at Harvard Medical School and leads the Program in Nutritional Metabolism at Massachusetts General Hospital. He served as the lead US investigator for the Egrifta clinical trials and his research spans visceral adipose tissue, cardiovascular

---

### Thymosin Alpha 1

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₁₂₉H₂₁₅N₃₃O₅₅ |
| molecular_weight | 3108.3 Da |
| synonyms | Thymalfasin, Zadaxin, Tα1, Talpha1, Alpha1-thymosin |
| cas_number | 62304-98-7 (also 69440-99-9, 69521-94-4) |
| sequence | Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN-OH (28 aa) |
| pubchem_cid | 16130571 |
| monoisotopic_mass | 3106.5041 g/mol |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | N/A |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 16130571
- inchi_key: NZVYCXVTEHPMHE-ZSUJOUNUSA-N
- inchi: InChI=1S/C129H215N33O55/...(full InChI — see PubChem CID 16130571)
- smiles_isomeric: CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)...(28-residue peptide — see PubChem CID 16130571)
- smiles_canonical: CCC(C)C(C(=O)NC(C(C)O)C(=O)NC(C(C)O)...(28-residue peptide — see PubChem CID 16130571)
- iupac_name: Thymosin Alpha 1 — N-acetylated 28-amino acid polypeptide (see PubChem CID 16130571 for full IUPAC)

**Overview:**

Thymosin Alpha 1 (Tα1), also known as thymalfasin (trade name Zadaxin), is a highly conserved, acidic polypeptide consisting of 28 amino acid residues with a molecular weight of 3,108.3 Da and an isoelectric point (pI) of 4.2. [1] [2]

        Origin: Tα1 was originally isolated from thymosin fraction 5 (TF5) — a crude extract from calf thymus — in 1977 by Dr. Allan L. Goldstein at the Albert Einstein College of research compound. [2] It is derived from a larger precursor protein called prothymosin alpha (ProTα) (109–111 amino acids) via cleavage by the lysosomal asparaginyl endopeptidase legumain (δ-secretase). [3]

        Structural Features: Linear polypeptide, N-terminally acetylated, no disulfide bonds, no glycosylation. In aqueous solution, Tα1 is intrinsically disordered; upon binding to membranes or receptors, it adopts an α-helix conformation (residues 14–26). [8]

        Regulatory Status:

        
          - International: Approved in 30+ countries (China, Italy, Asia, Latin America, Eastern Europe) for chronic hepatitis B, hepatitis C, and as a vaccine adjuvant/chemotherapy adjunct. [5]

          - FDA: Orphan compound designation for HCC, malignant melanoma, and DiGeorge anomaly. NOT generally registered for marketing. [6]

          - FDA Category 2: As of 2023/2024, placed on the Category 2 Bulk Drug Substances list, restricting compounding pharmacy use. [7]

          - WADA: May fall under broader banned peptide categories (note: Thymosin Beta-4 is explicitly prohibited; Tα1 status is context-dependent).

        

        Developer: Originally developed by Alpha 1 Biomedicals Inc.; commercial rights acquired by SciClone Pharmaceuticals, which launched Zadaxin globally. [9]

        Pharmacokinetic Highlights:

        
          - Half-Life: ~2 hours (serum)

          - Peak Levels: 1–2 hours post-subcutaneous injection

          - Urinary Excretion: 31–60% of administered dose

          - Route: Subcutaneous (standard clinical route)

          - Standard Clinical Dose: 1.6 mg SC (Zadaxin formulation)

**Mechanism of Action:**

### 1. Parent Molecule — Prothymosin Alpha

        Tα1 is the N-terminal fragment (residues 1–28) of the larger precursor protein prothymosin alpha (ProTα), an acidic nuclear protein of 109–111 amino acids involved in chromatin remodeling and cell proliferation. ProTα is cleaved by the lysosomal enzyme legumain (δ-secretase) to release the bioactive Tα1 peptide. [3]

        Structural Conformation: In aqueous solution, Tα1 is intrinsically unstructured (disordered). Upon interaction with negatively charged membranes (especially those exposing phosphatidylserine) or organic solvents, it adopts a structured conformation with an α-helix from residues 14–26 and two double β-turns in the N-terminal residues. [8]

        ### 2. Primary Receptor Targets

        Tα1 functions as a pleiotropic modulator by interacting with pattern recognition receptors (PRRs) and specific membrane components:

        
          - TLR9 and TLR2 Agonist: Signals through TLR9 in plasmacytoid dendritic cells (pDCs) and TLR2 in myeloid dendritic cells (mDCs). [4]

          - Membrane Interaction: N-terminal inserts into hydrophobic regions of cell membranes, particularly those exposing phosphatidylserine (PS) (found on apoptotic cells), triggering signal transduction.

          - Hyaluronic Acid (HA) Interaction: C-terminal “LKEKK” motif interacts electrostatically with HA, potentially interfering with CD44/RHAMM binding and suppressing tumor progression.

        

        ### 3. Downstream Signaling Cascades

        A. MyD88 → TRAF6 → IKK → NF-κB (Immune Activation):

        TLR9/TLR2 stimulation recruits the adaptor protein MyD88, activating TRAF6 → IKK complex → NF-κB transcription factor, promoting cytokine gene expression (IL-2, IFN-γ, IL-12). Often involves atypical PKC. [4] [10]

        B. p38 MAPK / JNK (DC Maturation):

        Tα1 induces phosphorylation of p38 MAPK and JNK (c-Jun N-terminal kinase). The p38 MAPK pathway is critical for dendritic cell maturation and production of Th1-priming cytokines. [11]

        C. cAMP / PKC (Anti-Apoptosis in Thymocytes):

        In thymocytes, Tα1 antagonizes steroid-induced apoptosis by stimulating cAMP production and activating PKC-dependent pathways.

        D. IDO1 Pathway → Immune Tolerance:

        Through TLR9 and Type I interferon receptor signaling, Tα1 induces IDO1 in dendritic cells, activating tryptophan catabolism (kynurenines), which promotes generation of regulatory T cells (Tregs) — inducing immune tolerance and dampening excessive inflammation/cytokine storms. [12]

        
          🔑 Dual Role: Tα1 uniquely provides both immune activation (NF-κB, MAPK → cytokines, T-cell maturation) AND immune tolerance (IDO1 → Tregs), depending on the immunological context. This dual capacity is central to its clinical versatility.

        
      The product supplied here is for research use only regardless of regulatory status of related formulations.

        ### 4. Cellular and Tissue-Level Effects

        Dendritic Cells:

        
          - Promotes functional maturation, increasing expression of HLA-DR, CD86, and CD40

          - Stimulates IL-12 production → drives Th1 phenotype (antiviral/antitumor) [4]

          - Can also promote tolerance via IDO1 pathway [12]

        
        T-Cells:

        
          - Promotes differentiation of stem cells into thymocytes

          - Increases activated CD4+ and CD8+ T cell numbers

          - Antagonizes glucocorticoid-induced apoptosis in immature thymocytes

        
        Macrophages:

        
          - Activates complement receptor (CR)-mediated phagocytosis (via actin/vinculin recruitment), distinct from Fc receptor mechanisms [13]

          - Dose-dependent response at 50–100 ng/mL

        
        Tumor Cells:

        
          - Upregulates MHC Class I expression, making tumors more visible to cytotoxic T cells

          - Can directly inhibit cell proliferation in certain cancer lines

        
        NK Cells:

        
          - Enhances NK cell activity and function [5]

        

        ### 5. Selectivity and Cross-Reactivity

        Tα1 acts as a “regulator of regulators” — modulating the sensitivity of TLRs to other stimuli (e.g., viral antigens) rather than solely acting as a direct agonist. It is highly conserved across mammalian species (human, bovine, porcine, ovine). [5]

        Distinct from Thymosin Beta-4 (TB-500): While Tα1 focuses on adaptive/innate immune modulation (TLR/T-cell maturation), TB-500 is primarily an actin-sequestering protein involved in cell motility, wound healing, and tissue repair.

        ### 6. Pharmacokinetics

        
          
            ParameterValue
          
          
            RouteSubcutaneous (standard)
            Peak Serum Levels1–2 hours post-SC injection
            Half-Life (T½)~2 hours
            Urinary Excretion31–60% of administered dose
            Dose-ResponseProportional Cmax/AUC for 0.8–6.4 mg single / 1.6–16 mg multiple
            AccumulationNo evidence of accumulation with repeated dosing
            Albumin BindingC-terminal residues 11–20 bind HSA (carrier)

**Research Applications:**

### 🦠 Viral Infections (Hepatitis B & C)

        Tα1 is most established for chronic Hepatitis B (CHB) and Hepatitis C (CHC). Clinical data demonstrates induction of HBeAg seroconversion, ALT normalization, and viral suppression, with synergistic effects when combined with interferon-alpha or nucleoside analogs. [5]

        ### 🎯 Oncology (Solid Tumors)

        Research demonstrates efficacy in malignant melanoma, hepatocellular carcinoma (HCC), and NSCLC. Tα1 is used as an adjuvant to chemotherapy (e.g., dacarbazine) or immunotherapy (e.g., ipilimumab), reducing tumor growth, increasing survival, and mitigating chemo-induced toxicity. [14] [15]

        ### 🏥 Sepsis

        In severe sepsis, Tα1 reverses immunosuppression by upregulating HLA-DR expression on monocytes and preventing lymphocyte apoptosis. The ETASS trial (n=361) showed 26% vs 35% mortality (P=0.049). [16]

        ### 🦠 COVID-19 / SARS

        During the COVID-19 pandemic, Tα1 was used in severe cases to restore lymphocytopenia and reverse T-cell exhaustion. A Wuhan retrospective study (n=76) showed 11.1% vs 58.8% mortality in severe cases. [17]

        ### 💉 HIV/AIDS

        Studied as adjunct to HAART, facilitating immune reconstitution by increasing CD4+ T-cell counts and sjTRECs (markers of thymic output). [18]

        ### 💉 Vaccine Adjuvant

        Enhances immunogenicity of influenza, H1N1, and HBV vaccines, particularly in immunocompromised populations (elderly, hemodialysis study subjects). In hemodialysis study subjects, 89% vs 53% seroconversion with H1N1 vaccine (P[19]

        ### 🫁 Cystic Fibrosis (CF)

        Tα1 has shown potential to correct maturation/activity of mutated F508del-CFTR protein while simultaneously reducing lung inflammation, though reproducibility has been debated. [20]

        ### 🍄 Fungal & Bacterial Infections

        Activates dendritic cells for Th1 resistance against invasive aspergillosis and enhances resistance to Pseudomonas in bone marrow transplant settings. [4]

        ### 🔬 Autoimmune Diseases

        study subjects with psoriatic arthritis, rheumatoid arthritis, and SLE exhibit lower serum Tα1 levels. Administration may restore immune homeostasis and regulate inflammation. [21]

**Research Summary:**

### Clinical Trials

        
          ✅ Thymosin Alpha 1 is one of the most clinically studied peptides in existence, with 10+ completed clinical trials and approval in 30+ countries as Zadaxin (thymalfasin).

        
        
          
            
              
                Trial
                Phase
                n=
                Indication
                Key Result
                Outcome
              
            
            
              ETASSPhase 3361Severe sepsis26% vs 35% mortality (P=0.049)✅ Positive
              TESTSPhase 31,106SepsisNo mortality benefit❌ Negative
              US HBVPhase 399Hepatitis B25% vs 13% (not significant)❌ Negative
              Japan HBVRCT316Hepatitis B36.4% ALT normalization✅ Positive
              HCV TripleRCT552Hepatitis C41% SVR vs 26.3% (P✅ Positive
              Wuhan COVIDRetro76Severe COVID-1911.1% vs 58.8% mortality✅ Positive
              MelanomaPhase 2488Metastatic melanoma9.4 vs 6.6 mo OS (P=0.08)✅ Trend
              NIBIT-M4F/U95Melanoma + Ipilimumab38.4 vs 8 mo OS (P=0.006)✅ Positive
              GASTO-1043Phase 2196NSCLC + chemoRT14.5% vs 35.4% pneumonitis✅ Positive
              H1N1 VaccinePilot122Hemodialysis study subjects89% vs 53% seroconversion✅ Positive
            
          
        

        ### Preclinical Animal Data (Selected)

        
          - Lung Cancer (LLC/H460): 0.25 mg/kg SC × 11 days — 40.5% tumor volume inhibition (LLC), 21.9% inhibition (H460). Promoted CD4+/CD8+ T cell infiltration. [22]

          - Melanoma (B16F10): Monotherapy reduced lung metastases by 32% (P[5]

          - Lung Adenoma Prevention: 0.4 mg/kg SC daily — reduced adenoma multiplicity by ~45% at 2.5 months.

          - Leukemia/Carcinoma Combo: Tα1 (200 µg/kg) + IL-2/IFN + cyclophosphamide achieved complete tumor regression in FLC and 3LL models. [23]

          - Sepsis (CLP): Tα1 + dexamethasone achieved highest survival rate; reversed DC depletion.

          - Immunosuppression: 100–1,000× more active than thymosin fraction 5 in restoring immunity in 5-FU models.

          - Aging: Restored antibody and T-cell responses in aged mice (23–24 months) to levels comparable to young animals. [24]

          - Arthritis (CIA): 0.25–1 mg/kg reduced paw volume, weight, and arthritic scores.

        

        ### Reported Tolerability Profile

        Tα1 is consistently reported as well-tolerated across 2,000+ clinical subjects. [1]

        
          - Common: Local injection site discomfort/redness (most frequent)

          - Rare: Fever, fatigue, muscle aches, nausea (usually when combined with IFN)

          - Hepatic: Transient ALT flares in HBV research application (often a sign of experimental effect)

          - Serious (rare): Fatal immune hemolytic anemia and engraftment failure in HSCT recipients

          - Preclinical: Single doses up to 20 mg/kg and 13-week repeated doses up to 6 mg/kg/day showed no adverse reactions

        
        Contraindications: Hypersensitivity to Tα1; organ transplant recipients (risk of rejection/GVHD via immune stimulation). [1]

      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (24 references):**

- Dominari A, Hathaway III D, Pandav K, et al. Thymosin alpha 1: A comprehensive review of the literature. World J Virol, 9(5), 67-78, 2020. — https://pubmed.ncbi.nlm.nih.gov/33024718/
- Goldstein AL, Low TL, McAdoo M, et al. Thymosin alpha1: Isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci USA, 74(2), 725-729, 1977. — https://pubmed.ncbi.nlm.nih.gov/265540/
- Li J, Liu CH, Wang FS. Thymosin alpha 1: biological activities, applications and genetic engineering production. Peptides, 31(11), 2151-2158, 2010. — https://pubmed.ncbi.nlm.nih.gov/20713107/
- Romani L, Bistoni F, Gaziano R, et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood, 103(11), 4232-4239, 2004. — https://pubmed.ncbi.nlm.nih.gov/14982876/
- King R, Tuthill C. Immune Modulation with Thymosin Alpha 1 research application. Vitamins and Hormones, 102, 151-178, 2016. — https://pubmed.ncbi.nlm.nih.gov/27450734/
- Pica F, Chimenti MS, Gaziano R, et al. Serum thymosin alpha 1 levels in study subjects with chronic inflammatory autoimmune diseases. Clin Exp Immunol, 186(1), 39-45, 2016. — https://pubmed.ncbi.nlm.nih.gov/27271610/
- FDA. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Tolerability Concerns. U.S. Food and Drug Administration, 2025. — https://www.fda.gov/drugs/human-compound-compounding/certain-bulk-compound-substances-use-compounding-may-present-significant-tolerability-risks
- Elizondo-Riojas MA, Chamow SM, Tuthill CW, et al. NMR structure of human thymosin alpha-1. Biochem Biophys Res Commun, 416(3-4), 356-61, 2011. — https://pubmed.ncbi.nlm.nih.gov/22108063/
- Billich A. Thymosin alpha1. SciClone Pharmaceuticals. Curr Opin Investig Drugs, 3(5), 698-707, 2002. — https://pubmed.ncbi.nlm.nih.gov/12090542/
- Garaci E. Thymosin alpha1: a historical overview. Ann N Y Acad Sci, 1112, 14-20, 2007. — https://pubmed.ncbi.nlm.nih.gov/17468232/
- Tao N, Xu X, Ying Y, et al. Thymosin alpha1 and Its Role in Viral Infectious Diseases: The Mechanism and Clinical Application. Molecules, 28(8), 3539, 2023. — https://pubmed.ncbi.nlm.nih.gov/37110752/
- Romani L, Bistoni F, Perruccio K, et al. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood, 108(7), 2265-74, 2006. — https://pubmed.ncbi.nlm.nih.gov/16788100/
- Serafino A, Pica F, Andreola F, et al. Thymosin alpha1 Activates Complement Receptor-Mediated Phagocytosis in Human Monocyte-Derived Macrophages. J Innate Immun, 6(1), 72-88, 2014. — https://pubmed.ncbi.nlm.nih.gov/23886925/
- Maio M, Mackiewicz A, Testori A, et al. Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in study subjects with metastatic melanoma. J Clin Oncol, 28(10), 1780-1787, 2010. — https://pubmed.ncbi.nlm.nih.gov/20195166/
- Costantini C, Bellet MM, Pariano M, et al. A Reappraisal of Thymosin Alpha1 in Cancer Therapy. Front Oncol, 9, 873, 2019. — https://pubmed.ncbi.nlm.nih.gov/31572678/
- Wu J, Zhou L, Liu J, et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Critical Care, 17(1), R8, 2013. — https://pubmed.ncbi.nlm.nih.gov/23327199/
- Liu Y, Pan Y, Hu Z, et al. Thymosin alpha-1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells. Clin Infect Dis, 71(16), 2150-2157, 2020. — https://pubmed.ncbi.nlm.nih.gov/32442287/
- Matteucci C, Grelli S, Balestrieri E, et al. Thymosin alpha 1 and HIV-1: recent advances and future perspectives. Future Microbiol, 12, 141-155, 2017. — https://pubmed.ncbi.nlm.nih.gov/28106473/
- Carraro G, Naso A, Montomoli E, et al. Thymosin-alpha 1 (Zadaxin) enhances the immunogenicity of an adjuvanted pandemic H1N1v influenza vaccine. Vaccine, 30(11), 2001-2004, 2012. — https://pubmed.ncbi.nlm.nih.gov/22245604/
- Romani L, Oikonomou V, Moretti S, et al. Thymosin alpha1 represents a potential potent single-molecule-based experimental protocol for cystic fibrosis. Nat Med, 23(5), 590-600, 2017. — https://pubmed.ncbi.nlm.nih.gov/28394333/
- Pica F, Chimenti MS, Gaziano R, et al. Serum thymosin alpha 1 levels in chronic inflammatory autoimmune diseases. Clin Exp Immunol, 186(1), 39-45, 2016. — https://pubmed.ncbi.nlm.nih.gov/27271610/
- Peng R, Xu C, Zheng H, et al. Modified Thymosin Alpha 1 Distributes and Inhibits the Growth of Lung Cancer in Vivo. ACS Omega, 5(18), 10374-10381, 2020. — https://pubmed.ncbi.nlm.nih.gov/32426589/
- Garaci E, Mastino A, Pica F, Favalli C. Combination research application using thymosin alpha 1 and interferon after cyclophosphamide is able to experimental endpoint Lewis lung carcinoma in mice. Cancer Immunol Immunother, 36(5), 355-359, 1993. — https://pubmed.ncbi.nlm.nih.gov/8467601/
- Simonova MA, Ivanov I, Shoshina NS, et al. Aging and Thymosin Alpha-1. Int J Mol Sci, 26(23), 11470, 2025. — https://pubmed.ncbi.nlm.nih.gov/39290867/

**Storage & Handling:**

Lyophilized: 2–8°C (refrigerated); -20°C for long-term desiccated storage. Reconstituted: use immediately or 4°C for 2–7 days. Standard clinical formulation: 1.6 mg/vial (Zadaxin).

**Author:** Dr. Allan L. Goldstein
Allan L. Goldstein, PhD, is Professor Emeritus at the George Washington University (GW) School of research compound and Health Sciences. He originally isolated and characterized Thymosin Alpha 1 from thymic tissue (thymosin fraction 5) in 1977 at the Albert Einstein College of research compound, est

---

### Tirzepatide

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C225H348N48O68 |
| molecular_weight | 4813.45 g/mol |
| synonyms | Mounjaro, Zepbound (Generic references) |
| cas_number | 2023788-19-2 |
| sequence | Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{diacid-C20-gamma-Glu-(AEEA)2-Lys}-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 |
| pubchem_cid | 163340162 |

**Storage & Handling:**

Store at 2°C to 8°C (36°F to 46°F).

---

### Vip

**Chemical Properties:**

| Property | Value |
|----------|-------|
| formula | C₁₄₇H₂₃₈N₄₄O₄₂S |
| molecular_weight | 3326.8 Da |
| synonyms | Vasoactive Intestinal Peptide, Aviptadil, RLF-100, Zyesami, Vasoactive Intestinal Polypeptide |
| cas_number | 37221-79-7 |
| sequence | His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ |
| pubchem_cid | 16129630 |
| monoisotopic_mass | N/A |
| polar_area | N/A |
| complexity | N/A |
| x_log_p | N/A |
| heavy_atom_count | N/A |
| h_bond_donor_count | N/A |
| h_bond_acceptor_count | N/A |
| rotatable_bond_count | N/A |

**Identifiers:**
- pubchem_cid: 16129630
- inchi_key: N/A — 28-amino acid peptide (full InChI via PubChem CID 16129630)
- inchi: N/A — 28-amino acid peptide (full InChI via PubChem CID 16129630)
- smiles_isomeric: N/A — 28-amino acid peptide (full SMILES via PubChem CID 16129630)
- smiles_canonical: N/A — 28-amino acid peptide (full SMILES via PubChem CID 16129630)
- iupac_name: Vasoactive Intestinal Peptide — 28-amino acid neuropeptide of the glucagon-secretin superfamily

**Overview:**

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid signaling neuropeptide belonging to the glucagon-secretin superfamily. [1] It is a highly conserved molecule across mammalian evolution, identical in humans, pigs, rats, and cows. VIP was originally isolated from the porcine duodenum by Sami I. Said and Viktor Mutt in 1970 at the Medical College of Virginia and Karolinska Institute, respectively. [2]

        VIP is derived from a larger precursor molecule, prepro-VIP (170 amino acids), encoded by the VIP gene on chromosome 6 in humans. Prepro-VIP is processed into pro-VIP (149 amino acids), which is further cleaved and amidated by peptidylglycine alpha-amidating monooxygenase to produce the mature, C-terminally amidated 28-amino acid peptide. [6]

        VIP is widely distributed in the central and peripheral nervous systems and is produced by neurons, endocrine cells, and immune cells (B-lymphocytes and T-lymphocytes). It exerts potent anti-inflammatory, immunomodulatory, and vasodilatory properties. [3]

        The synthetic form, Aviptadil (also known as RLF-100 or Zyesami), has received FDA Orphan compound Designation for the investigation of ARDS, pulmonary hypertension, and sarcoidosis, and Fast Track Designation for critical COVID-19 with respiratory failure. The EMA has granted Orphan compound Designation for ARDS and sarcoidosis. In India, the CDSCO approved Aviptadil for emergency use in COVID-19 ARDS in 2022. [4]

        VIP has an extremely short serum half-life of approximately 1–2 minutes, due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) and other serum peptidases. This lability presents significant pharmacological challenges and has driven research into advanced delivery systems including sterically stabilized micelles (SSM), liposomes, and inhalation formulations. [5]

        VIP shares 68% homology with PACAP-27 and is reported to be 100-fold more potent than isoproterenol as a bronchodilator and 50-fold more potent than prostacyclin at relaxing pulmonary arteries. [7]

**Mechanism of Action:**

### 1. Primary Receptor Targets — VPAC1, VPAC2, and PAC1

        VIP exerts its biological effects primarily by binding to two specific G-protein-coupled receptors (GPCRs) belonging to the Class B (secretin-like) family: [3]

        
          - VPAC1 (VIPR1): Constitutively expressed in the lung (alveolar type II cells), T-lymphocytes, liver, and brain cortex.

          - VPAC2 (VIPR2): Predominantly expressed in smooth muscle, the suprachiasmatic nucleus (SCN), pancreatic β-cells, and inducible in immune cells upon stimulation.

          - PAC1: VIP also binds to the PACAP receptor PAC1, but with significantly lower affinity (>500 nM). [8]

        
        VIP-receptor interaction follows a “two-site” binding model: the N-terminal ectodomain (structured as a “Sushi” domain) captures VIP’s central/C-terminal regions (residues 6–28), then the N-terminus of VIP (His1) activates transmembrane domain 1 (TM1). [9]

        ### 2. Canonical Signaling — Gs/cAMP/PKA/CREB Pathway

        In most cell types, VIP binding triggers the exchange of GDP for GTP on the Gαs subunit, activating adenylyl cyclase (AC) and increasing intracellular cyclic AMP (cAMP). Elevated cAMP activates Protein Kinase A (PKA), which phosphorylates cAMP response element-binding protein (CREB). This pathway drives surfactant production in lungs and insulin secretion in the pancreas. [10]

        ### 3. Alternative Signaling Pathways

        
          - NF-κB Inhibition (PKA-Independent): In macrophages and monocytes, VIP inhibits nuclear translocation of NF-κB through a PKA-independent mechanism that prevents phosphorylation of IκB and inhibits IκB kinase (IKK), suppressing pro-inflammatory cytokine production. [11]

          - Dual Gs/AC + Gq/PLC Pathway (Neurons): In GnRH neurons, VIP excitation requires both Gs/AC/PKA and Gq/Phospholipase C (PLC) activation, leading to PIP2 depletion and inhibition of KCa3.1 channels. [12]

          - Epac Pathway (β-Cells): In pancreatic β-cells, VIP signaling involves both PKA (closing ATP-dependent K⁺ channels, causing depolarization and Ca²⁺ influx) and the Epac pathway (mobilizing intracellular Ca²⁺ stores to drive insulin secretion). [13]

          - EGFR/HER2 Transactivation (Cancer): In certain cancer cells (lung, breast), VIP/PACAP signaling can transactivate EGFR and HER2, promoting cell growth and VEGF secretion. [14]

        

        ### 4. Tissue-Level Effects

        Immunomodulation: VIP inhibits production of pro-inflammatory cytokines (TNF-α, IL-6, IL-12) and chemokines in macrophages and microglia. It shifts T-cell differentiation from Th1 toward Th2 and Treg phenotypes, and downregulates TLR2 and TLR4 expression on macrophages and dendritic cells. [11]

        Pulmonary System: VIP upregulates choline phosphate cytidylyltransferase and C-Fos protein in alveolar type II (ATII) cells, increasing surfactant production. It acts as a potent bronchodilator — 100-fold more potent than isoproterenol. [15]

        Central Nervous System: In the suprachiasmatic nucleus (SCN), VIP synchronizes neuronal firing via VPAC2, producing long-lasting increases in electrical activity (2–4 hours) dependent on the clock gene Per1 and Kv3 channels. [16]

        Metabolic System: VIP stimulates insulin secretion in a glucose-dependent manner via VPAC2 receptors on pancreatic β-cells — negligible at low glucose (protecting against hypoglycemia) but potent during hyperglycemia. [13]

        ### 5. Pharmacokinetics — Ultra-Short Half-Life

        VIP has a serum half-life of approximately 1–2 minutes, with rapid degradation by DPP-4 and other peptidases in the liver, kidneys, and lung. [5] Following IV administration, approximately 45% of the dose distributes to the lungs within 30 minutes. Apparent volume of distribution is ~14 mL/kg with a metabolic clearance rate of ~9 mL/kg/min. [17]

        ### 6. Dose-Response Relationships

        
          - CNS Firing Rate (SCN): 1 µM and 10 µM VIP produced significant increases in SCN neuronal firing; 0.1 µM had no effect (threshold response). [16]

          - Circadian Phase Shifting: Threshold ~100 nM, EC₅₀ ~500 nM, saturation at ~10 µM. [18]

          - Neuroprotection (VIPR2 agonist LBT-3627): Bell-shaped dose-response — 2.0 mg/kg provided optimal neuroprotection and Treg rescue in rat Parkinson’s models. [19]

          - Antiviral Activity: 10 nM VIP provided maximal anti-SARS-CoV-2 effects in cell models; effects seen at 1 nM. [4]

**Research Applications:**

### 🫁 ARDS & COVID-19 (Aviptadil)

        Aviptadil has been investigated for critical respiratory failure because it protects alveolar type II cells and blocks cytokine storm. In the Phase 2b/3 trial (NCT04311697, n=196), IV aviptadil achieved a twofold increase in 60-day survival (OR 2.0; p=0.035) and a 10-fold increase in survival among mechanically ventilated study subjects, with significant IL-6 reduction. The larger TESICO trial (n=461) was stopped for futility. [4] [20]

        ### 🧠 Neurodegenerative Disorders (Parkinson’s & Alzheimer’s)

        VIP acts as a neuroprotective agent by deactivating microglia and inhibiting neurotoxin release (TNF-α, IL-1β). In Parkinson’s models, the VIPR2 agonist LBT-3627 (2.0 mg/kg) increased surviving dopaminergic neurons by 43% and reduced reactive microglia by 57–61%. In Alzheimer’s models, VIP protects against β-amyloid toxicity via ADNP induction. [19] [21]

        See also: BPC-157 for related neuroprotective research.

        ### 🔬 Inflammatory Bowel Disease (IBD)

        VIP maintains intestinal barrier homeostasis. VIP-loaded sterically stabilized micelles (VIP-SSM) reversed severe colitis in DSS mouse models with a single experimental dose, restoring tight junction protein occludin and chloride transporter DRA expression. Free VIP required alternate-day dosing for comparable effects. [22]

        ### 🎯 Oncology Imaging (VPAC1 PET)

        VPAC1 receptors are overexpressed in breast, prostate, colon, and lung cancers. Radiolabeled VIP analogues (⁶⁴Cu-VIP, ¹²³I-VIP, Tc-99m-TP3654) enable PET imaging of tumors — achieving 87% primary detection in colorectal cancer and 100% lymph node metastasis detection. ⁶⁴Cu-VIP also detected grade IV prostate neoplasia undetectable by standard ¹⁸F-FDG PET or CT. [23] [24]

        ### ❤️ Pulmonary Hypertension

        Inhaled VIP (100–200 µg) caused potent pulmonary vasodilation in 20 study subjects — decreased pulmonary artery pressure and vascular resistance, improved mixed venous oxygen saturation, and increased cardiac output — without significant systemic reported observations in study populations. VIP is 50-fold more potent than prostacyclin at relaxing pulmonary arteries. [7]

        ### 🫁 Sarcoidosis

        In a Phase II trial (n=20), nebulized VIP (50 µg, 4x daily for 4 weeks) exerted immunoregulatory effects in study subjects with active sarcoidosis — significantly reducing TNF-α production in bronchoalveolar lavage (BAL) fluid and increasing regulatory T-cell counts. No systemic immunosuppression or obvious reported observations in study populations. [25]

        ### ⏰ Circadian Rhythm Regulation

        The suprachiasmatic nucleus (SCN) relies on VIP signaling to synchronize cellular circadian clocks to environmental light cycles. VIP application phase-shifts circadian rhythms, with pulsing rapidly resetting rhythm via swift reduction of PER2 protein. VIP is necessary for synchronization of SCN neurons, influencing sleep and hormonal cycles. [16]

        ### 🦠 Sepsis

        In a Phase I trial (n=8), IV aviptadil (50–100 pmol/kg/hr for 12 hours) achieved 75% survival (6/8) in sepsis-induced ARDS. VIP inhibits high levels of inflammatory cytokines and is viewed as a potential adjunctive experimental protocol to antibiotics for septic shock management. [26]

**Research Summary:**

### Animal Studies

        
          - Parkinson’s Disease (Rats, Mosley 2019): VIPR2 agonist LBT-3627 at 2.0 mg/kg SC — 43% increase in surviving TH+ neurons (α-Syn model), 53% spared at 6.0 mg/kg (6-OHDA model), 57–61% reduction in reactive microglia. [19]

          - Parkinson’s Disease (Mice, Delgado 2003): VIP in MPTP model prevented dopaminergic neuronal loss and microglial activation; blocked iNOS, IL-1β, TNF-α expression. [21]

          - IBD/Colitis (Mice, Jayawardena 2017): VIP-SSM single dose reversed severe DSS colitis (P[22]

          - PET Imaging (Mice, Zhang 2007/2008): ⁶⁴Cu-VIP analogues in breast/prostate xenografts — tumor:normal uptake ratios 2.17–10.93, >85% ⁶⁴Cu retention in blood. Detected grade IV prostate neoplasia undetectable by FDG-PET. [23]

          - Diabetes (Rats, Tsutsumi 2002): VPAC2 agonist BAY 55-9837 stimulated glucose-dependent insulin secretion without hypoglycemia. [13]

          - Cardiovascular tolerability (Dogs, Mosley 2019): LBT-3627 at 0.14–1.4 mg/kg SC — transient hemodynamic effects only at doses >experimental threshold; resolved within 4 hours. [19]

          - SCN Circadian (Mice, Kudo 2013): 1 µM VIP increased SCN neuronal firing rate (P[16]

        

        ### Human Clinical Trials

        
          - COVID-19 ARDS Phase 2b/3 (NCT04311697, n=196): IV aviptadil 50/100/150 pmol/kg/hr × 3 days. Failed primary endpoint; 2× survival at 60 days (OR 2.0, p=0.035), 10× survival in ventilated study subjects. IL-6 significantly reduced. [4]

          - TESICO (NCT04843761, n=461): IV aviptadil for COVID-19 hypoxemic respiratory failure. No benefit; stopped for futility. 90-day mortality 38% vs 36% placebo. [20]

          - Inhaled COVID-19 Phase II (NCT04844580, n=80): Inhaled aviptadil × 5 days. Failed primary (hospital discharge); significant improvement in dyspnea (p=0.033) and CT scores (p=0.028). [27]

          - Sarcoidosis Phase II (n=20): Nebulized VIP 50 µg 4x daily × 4 weeks. Reduced TNF-α, increased Tregs in BAL fluid. No systemic immunosuppression. [25]

          - Pulmonary Hypertension (n=20): Inhaled VIP 100–200 µg. Decreased PA pressure, increased cardiac output. Temporary effect. [7]

          - Septic ARDS Phase I (n=8): IV aviptadil 50–100 pmol/kg/hr × 12 hours. 6/8 survived; tolerability established. [26]

          - Tumor Imaging (Various): ¹²³I-VIP and Tc-99m-TP3654 IV. 87% detection in primary colorectal, 100% lymph node metastases. [23]

          - India COVID-19 ARDS (n=150): IV aviptadil ascending doses × 3 days. 80% vs 76% survival (not significant). Improved PaO₂/FiO₂. [28]

        

        ### Regulatory Status

        FDA: Orphan compound Designation (ARDS, pulmonary hypertension, sarcoidosis); Fast Track Designation (critical COVID-19).

        EMA: Orphan compound Designation (ARDS, sarcoidosis).

        CDSCO (India): registered for emergency use in COVID-19 ARDS (2022).

        reported tolerability profile: Most common AEs: hypotension (26%), diarrhea (33% — reproduces “pancreatic cholera” syndrome), facial flushing, tachycardia. No compound-related serious AEs or mortality in controlled trials. Contraindicated in refractory hypotension, severe diarrhea, end-stage liver disease, and pregnancy. [4]

      
        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

**Citations (28 references):**

- Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science, 169(3951), 1217–1218, 1970. — https://pubmed.ncbi.nlm.nih.gov/4988715/
- Said SI, Rosenberg RN. Vasoactive intestinal polypeptide: abundant immunoreactivity in neuronal cell lines and normal nervous tissues. Science, 192(4242), 907–908, 1976. — https://pubmed.ncbi.nlm.nih.gov/1273576/
- Langer I, Jeandriens J, Couvineau A, et al. Signal transduction by VIP and PACAP receptors. Biochem Soc Trans, 50(1), 2022. — https://pubmed.ncbi.nlm.nih.gov/35015869/
- Youssef JG, Lavin P, Schoenfeld DA, et al. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in study subjects With Critical COVID-19 Respiratory Failure. Crit Care Med, 50(11), 1545–1554, 2022. — https://pubmed.ncbi.nlm.nih.gov/35776677/
- Domschke S, Domschke W, Bloom SR, et al. Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut, 19(11), 1049–1053, 1978. — https://pubmed.ncbi.nlm.nih.gov/730072/
- Harmar AJ, Arimura A, Gozes I, et al. International union of pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev, 50(2), 265–270, 1998. — https://pubmed.ncbi.nlm.nih.gov/9647867/
- Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J, 32(5), 1289–1294, 2008. — https://pubmed.ncbi.nlm.nih.gov/18579542/
- Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev, 56(2), 249–290, 2004. — https://pubmed.ncbi.nlm.nih.gov/15169929/
- Couvineau A, Laburthe M. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol, 166(1), 42–50, 2012. — https://pubmed.ncbi.nlm.nih.gov/21951273/
- Hou X, Yang H, Bhatt VR, et al. VIP/VPAC signaling in pancreatic islet β-cells and glucose homeostasis. J Mol Endocrinol, 68(3), R65–R75, 2022. — https://pubmed.ncbi.nlm.nih.gov/35099406/
- Smalley SG, Barrow PA, Foster N. Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its experimental potential in inflammatory disease. Clin Exp Immunol, 157(2), 225–234, 2009. — https://pubmed.ncbi.nlm.nih.gov/19604263/
- Constantin S, Bhattarai JP, Bhatt R, et al. VIP signaling in GnRH neurons involves dual Gs/AC and Gq/PLC pathways. J Neuroendocrinol, 36(4), e13392, 2024. — https://pubmed.ncbi.nlm.nih.gov/38622012/
- Hou X, et al. VIP/VPAC signaling in pancreatic islet β-cells: PKA and Epac pathways drive glucose-dependent insulin secretion. J Mol Endocrinol, 2022. — https://pubmed.ncbi.nlm.nih.gov/35099406/
- Moody TW, Nuche-Berenguer B, Jensen RT. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes, 23(1), 38–47, 2016. — https://pubmed.ncbi.nlm.nih.gov/26588233/
- Mathioudakis AG, Chatzimavridou-Grigoriadou V, Evangelopoulou E, Mathioudakis GA. Vasoactive Intestinal Peptide Inhaled Agonists: Potential Role in Respiratory Therapeutics. Hippokratia, 17(1), 12–16, 2013. — https://pubmed.ncbi.nlm.nih.gov/23935337/
- Kudo T, Tahara Y, Gamble KL, et al. Vasoactive intestinal peptide produces long-lasting changes in neural activity in the suprachiasmatic nucleus. J Neurophysiol, 110(5), 1097–1106, 2013. — https://pubmed.ncbi.nlm.nih.gov/23761697/
- Said SI. Vasoactive intestinal peptide in the lung. Ann N Y Acad Sci, 527, 450–464, 1988. — https://pubmed.ncbi.nlm.nih.gov/2841882/
- An S, Tsai C, Bhatt R, et al. Vasoactive intestinal polypeptide phase-shifts the circadian clock via cAMP/PKA dependent pathway. J Biol Rhythms, 26(4), 313–326, 2011. — https://pubmed.ncbi.nlm.nih.gov/21775290/
- Mosley RL, Lu Y, Olson KE, et al. A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson’s Disease. Front Cell Neurosci, 13, 421, 2019. — https://pubmed.ncbi.nlm.nih.gov/31616253/
- Brown SM, Barkauskas CE, Grund B, et al. Intravenous aviptadil and remdesivir for investigation of COVID-19-associated hypoxaemic respiratory failure (TESICO). Lancet Respir Med, 11(9), 791–803, 2023. — https://pubmed.ncbi.nlm.nih.gov/37354912/
- Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J, 17(8), 944–946, 2003. — https://pubmed.ncbi.nlm.nih.gov/12626429/
- Jayawardena D, Guzman G, Gill RK, et al. Expression and localization of VPAC1, the major receptor of vasoactive intestinal peptide along the length of the intestine. Am J Physiol Gastrointest Liver Physiol, 313(1), G16–G25, 2017. — https://pubmed.ncbi.nlm.nih.gov/28408644/
- Virgolini I, Raderer M, Kurtaran A, et al. Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors. N Engl J Med, 331, 1116–1121, 1994. — https://pubmed.ncbi.nlm.nih.gov/7935636/
- Zhang K, Aruva MR, Shanthly N, et al. PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer. J Nucl Med, 49(1), 112–121, 2008. — https://pubmed.ncbi.nlm.nih.gov/18077525/
- Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med, 182(4), 540–548, 2010. — https://pubmed.ncbi.nlm.nih.gov/20442436/
- Youssef JG, Said SI, et al. Rapid clinical recovery from critical COVID-19 with respiratory failure in a lung transplant patient treated with intravenous vasoactive intestinal peptide. Preprints, 2020. — https://pubmed.ncbi.nlm.nih.gov/35776677/
- Esendagli D, Sarı N, Akhan S, et al. Inhaled Aviptadil Is a New Hope for Recovery of Lung Damage due to COVID-19. Med Princ Pract, 34(2), 191–200, 2025. — https://pubmed.ncbi.nlm.nih.gov/39693552/
- Dewan B, Shinde S. Aviptadil in acute respiratory distress syndrome associated with covid-19 infection. Eur J Pharm Med Res, 9(6), 243–253, 2022. — https://pubmed.ncbi.nlm.nih.gov/35776677/

**Storage & Handling:**

Lyophilized: Store at -20°C, desiccated, protect from light. Reconstituted: Use immediately. ~1–2 min half-life — extremely labile peptide.

**Author:** Dr. Sami I. Said
Sami I. Said, MD, is the co-discoverer of VIP, originally isolating the peptide from porcine intestine in 1970 at the Medical College of Virginia alongside Viktor Mutt of Karolinska Institute. He subsequently joined Stony Brook University (SUNY), where he identified VIP in the central and peripheral

---

## Research Articles

### Synergistic Regeneration: BPC-157, Thymosin Beta-4, and GHK-Cu in Healing

**Author:** Dr. Hannah | **Category:** Peptide Combinations | **Read Time:** 8 min read

**Summary:**
BPC-157, Thymosin Beta-4 (TB-500), and GHK-Cu have each been extensively studied for their powerful roles in tissue repair, inflammation modulation, and cellular regeneration. These three peptides have independently demonstrated impressive therapeutic potential across a wide range of physiological systems including accelerating wound healing, supporting angiogenesis, reducing fibrosis, and modulating immune responses. While their mechanisms of action differ, they share a common goal: restoring balance and promoting optimal tissue function following injury or physiological stress.
            

            
                This article will explore the emerging science behind understanding the research potential of these peptides in combination, where their complementary biological actions may create a synergistic effect—amplifying healing, recovery, and systemic resilience beyond what each compound achieves alone. By examining the latest data and mechanistic insights, we aim to provide a deeper understanding of how BPC-157, TB-500, and GHK-Cu may work together to support advanced tissue regeneration, performance optimization, and long-term health span.

**Full Content:**
In the evolving landscape of regenerative biology, three peptides have risen to the forefront of research: BPC-157, Thymosin Beta-4 (TB-500), and GHK-Cu. While each has been extensively studied for their individual capabilities in tissue repair and inflammation modulation, the scientific community is now turning its attention to their potential synergy.
                

                
                    These compounds share a unified goal: the restoration of homeostasis and the optimization of tissue function following physiological stress. However, they achieve this through distinct, non-overlapping mechanisms. This article examines the hypothesis that combining these agents creates a "multi-modal" healing environment—where angiogenesis, cellular migration, and matrix remodeling occur simultaneously to accelerate recovery.
                

                ### BPC-157: The Angiogenic Architect

                
                    Body Protection Compound-157 (BPC-157) is a pentadecapeptide derived from a protein found in gastric juice. Its primary claim to fame in research models is its profound cytoprotective and angiogenic properties.
                

                
                    - Vascular Defense: BPC-157 is observed to upregulate Vascular Endothelial Growth Factor (VEGF), promoting the formation of new capillaries (angiogenesis). This restoration of blood flow is critical for delivering oxygen and nutrients to damaged sites.

                    - Tendon & Gut Axis: Unique among peptides, BPC-157 has shown efficacy in healing avascular tissues like tendons and ligaments, as well as maintaining the integrity of the gut lining against NSAID-induced damage.

                

                ### TB-500: The Cellular Mobilizer

                
                    Thymosin Beta-4, often researched as its synthetic fragment TB-500, operates on the cytoskeleton of the cell itself. Its primary mechanism involves the sequestration of actin monomers.
                

                
                    #### Key Mechanism: Actin Sequestration

                    
                        By binding to actin, TB-500 prevents the premature polymerization of filaments. This keeps the cellular structure flexible, allowing cells to migrate rapidly to the site of an injury. In essence, it "unlocks" the cells, enabling them to move where they are needed most to close wounds and regenerate tissue.
                    

                
                
                    Furthermore, TB-500 is distinct in its anti-fibrotic potential. Research suggests it can downregulate the differentiation of myofibroblasts, the cells responsible for scar tissue formation, thereby promoting "scarless" healing.
                

                ### GHK-Cu: The Remodeling Agent

                
                    GHK-Cu (Glycyl-L-Histidyl-L-Lysine Copper) is a naturally occurring tripeptide with a high affinity for copper ions. Discovered in human plasma, its levels decline significantly with age, which correlates with slower healing rates in older populations.
                

                
                    GHK-Cu acts as a signal to reset the genetic expression of cells to a healthier state. It is a potent stimulator of collagen and elastin synthesis, but critically, it also modulates the breakdown of collagen. This dual action ensures that the extracellular matrix is not just built, but built correctly, avoiding the disorganized structure typical of scarring.
                

                ### The Theory of Synergy

                
                    When used in combination, these three peptides attack the problem of injury from all angles:
                

                
                    - Supply Lines (BPC-157): First, BPC-157 establishes the vascular network, ensuring the injury site is perfused with blood and raw materials.

                    - Workforce Mobilization (TB-500): TB-500 mobilizes the repair cells, allowing them to travel via the new blood vessels to the specific site of damage.

                    - Construction & Finish (GHK-Cu): Finally, GHK-Cu provides the copper cofactors and genetic signaling required to lay down high-quality collagen and elastin, ensuring the final repair is structurally sound and aesthetically refined.

                
                
                ### Conclusion

                
                    While human clinical trials are still needed to fully validate these protocols, preclinical data suggests that the combination of BPC-157, TB-500, and GHK-Cu represents a sophisticated, biological approach to healing. By leveraging the body's own repair mechanisms—vascular growth, cell motility, and matrix remodeling—researchers can explore new frontiers in recovery and longevity.

---

### Cardiogen: A Heart-Specific Peptide Bioregulator

**Author:** Dr. Hannah | **Category:** Bioregulators | **Read Time:** 5 min read

**Summary:**
Cardiogen represents a unique class of peptides known as "bioregulators." Unlike varying signaling hormones, bioregulators are short chains of amino acids that interact directly with the DNA structure to modulate gene expression. Originally synthesized based on analysis of cardiac tissue, Cardiogen is designed to support the heart at a cellular level.
            

            
                 It does not force the heart to beat faster or slower; rather, it "coaches" heart cells to repair themselves and maintain efficient energy metabolism. By targeting the fundamental genetic regulation of cardiac tissue, it offers a distinct pathway from traditional cardiovascular interventions, focusing on resilience and repair rather than mere symptom management.

**Full Content:**
Cardiogen represents a unique class of peptides known as "bioregulators." Unlike varying signaling hormones, bioregulators are short chains of amino acids that interact directly with the DNA structure to modulate gene expression.
                

                
                    Originally synthesized based on analysis of cardiac tissue, Cardiogen is designed to support the heart at a cellular level. It does not force the heart to beat faster or slower; rather, it "coaches" heart cells to repair themselves and maintain efficient energy metabolism.
                

                
                ### Mechanism: Epigenetic Modulation

                
                    The primary theory behind Cardiogen's function is its ability to penetrate the cell nucleus and bind to specific genes related to cardiac function. By doing so, it may upregulate the synthesis of proteins required for the maintenance of heart muscle cells (cardiomyocytes).
                

                
                    In animal models of cardiac injury and aging, Cardiogen has shown promise in:
                

                
                    - Improving Mitochondrial Efficiency: Enhancing the way heart cells utilize oxygen and produce ATP.

                    - Reducing Fibrosis: Limiting the formation of scar tissue in the heart following stress or injury.

                    - Promoting Resilience: Increasing the tissue's resistance to oxidative stress.

                

                ### Summary

                
                    Cardiogen remains a subject of intense interest for its potential to support long-term heart health. By targeting the fundamental genetic regulation of cardiac tissue, it offers a distinct pathway from traditional cardiovascular interventions.

---

### BPC-157: Mechanisms of Angiogenesis and Wound Healing

**Author:** Dr. Hannah | **Category:** Recovery Compound | **Read Time:** 6 min read

**Summary:**
Body Protection Compound-157 (BPC-157) has become a focal point in regenerative medicine due to its profound ability to accelerate the healing of soft tissues, particularly tendons, ligaments, and the gastrointestinal tract. This 15-amino-acid peptide, derived from a protein in gastric juice, exhibits remarkable stability and efficacy across various administration routes.
            

            
                A seminal study by Huang et al. (2015) utilized a localized drug delivery system to explore the peptide's efficacy. The results demonstrated that BPC-157 significantly accelerates wound closure rates in animal models. The study highlighted a key mechanism: the upregulation of Vascular Endothelial Growth Factor (VEGF), which stimulates the formation of new capillaries (angiogenesis) to "re-vascularize" damaged tissues.

**Full Content:**
Body Protection Compound-157 (BPC-157) has become a focal point in regenerative medicine due to its profound ability to accelerate the healing of soft tissues, particularly tendons, ligaments, and the gastrointestinal tract.
                

                ### Evidence from In Vivo Studies

                
                    A seminal study by Huang et al. (2015) utilized a localized drug delivery system to explore the peptide's efficacy. The results demonstrated that BPC-157 significantly accelerates wound closure rates in animal models. The study highlighted a key mechanism: the upregulation of Vascular Endothelial Growth Factor (VEGF).
                

                
                    VEGF is the signal protein that stimulates the formation of blood vessels. By increasing VEGF expression, BPC-157 effectively "re-vascularizes" damaged tissue. This is particularly critical for tendons and ligaments, which notoriously suffer from poor blood supply, leading to slow recovery times.
                

                ### Stability and Systemic Effects

                
                    Further research by Vukusić et al. (2020) focused on the stability of the pentadecapeptide. Unlike many peptides that degrade rapidly, BPC-157 remains stable in human gastric juice for over 24 hours. This stability allows for diverse administration routes (oral, topical, or systemic) while maintaining biological activity.
                

                
                    #### Key Research Finding

                    
                        "BPC 157 accelerates the healing of various wounds, including alkali burns and diabetic ulcers, by modulating the NO-cGMP pathway, which controls blood flow and tissue repair signaling." — Vukusić et al., Frontiers in Pharmacology (2020)
                    

                

                ### Conclusion

                
                    Current literature suggests BPC-157 acts as a comprehensive "healing coordinator," promoting angiogenesis and protecting cell survival under stress.
                

                
                #### Sources

                
                    - Huang T. et al. (2015). BPC-157 enhances wound healing in vivo. Drug Des Devel Ther.

                    - Vukusić D. et al. (2020). Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol.

---

### Thymosin Beta-4: The Cellular Driver of Repair

**Author:** Dr. Hannah | **Category:** Recovery Compound | **Read Time:** 7 min read

**Summary:**
Thymosin Beta-4 (TB-500) is a naturally occurring protein present in nearly all human cells, playing a vital role in the cytoskeletal structure. Research spanning decades has elucidated its potential as a powerful regenerative therapy, primarily through the mechanism of actin sequestration.
            

            
                As established by Goldstein et al. (2012) and Sosne et al. (2016), TB-4 regulates actin polymerization, which directly increases cell motility. In the context of injury, this means that keratinocytes and endothelial cells can migrate more rapidly to cover open wounds. This "gap closing" speed is a critical factor in preventing infection and reducing scarring, making TB-4 a key player in both corneal and dermal healing.

**Full Content:**
Thymosin Beta-4 (TB-500) is a naturally occurring protein that plays a vital role in the cytoskeletal structure of cells. Research spanning decades has elucidated its potential as a powerful regenerative therapy.
                

                ### Cell Migration and Dermal Healing

                
                    As established by Goldstein et al. (2012) and Sosne et al. (2016), the primary mechanism of TB-4 is actin sequestration. By regulating actin polymerization, TB-4 increases cell motility.
                

                
                   In the context of a skin wound or corneal injury, this means keratinocytes and endothelial cells can migrate more rapidly to cover the open wound. This "gap closing" speed is a critical factor in preventing infection and reducing scarring.
                

                ### Recent Developments (2025)

                
                    A comprehensive review by Chandrasekaran et al. (2025) highlighted the synergistic potential of TB-4 when combined with trace elements like Selenium. The review suggests that TB-4's ability to modulate inflammation, combined with antioxidant support, creates an optimal environment for healing difficult wounds, such as diabetic ulcers.
                

                 
                    #### Clinical Implication

                    
                        TB-4 is not just a growth factor; it is an anti-inflammatory modulator. It has been shown to reduce the expression of pro-inflammatory cytokines, preventing the chronic inflammation that often stalls healing in aging tissues.
                    

                

                #### Sources

                
                    - Goldstein A.L. et al. (2012). Thymosin β4: basic properties and clinical applications. Expert Opin Biol Ther.

                    - Sosne G. et al. (2016). Thymosin β4 promotes dermal healing. Vitam Horm.

                    - Chandrasekaran V.N. et al. (2025). Combined impact of Thymosin β4... Discover Biotechnol.

---

### GHK-Cu: Genetic Modulation and Skin Regeneration

**Author:** Dr. Hannah | **Category:** Longevity Research | **Read Time:** 5 min read

**Summary:**
The copper peptide GHK-Cu is unique among regenerative agents because its effects appear to be largely epigenetic. It does not merely stimulate a receptor; it modulates the expression of thousands of human genes, essentially pressing a "reset button" on cells to return them to a more youthful metabolic state.
            

            
                Greenfield et al. (2018) analyzed the effect of GHK on gene expression using genomic databases and found that it induces a signature that opposes aging—suppressing tissue destruction and inflammation while upregulating repair. Furthermore, Pickart (2018) highlighted its role in skin biology, where it facilitates tight remodeling by balancing collagen breakdown and synthesis, leading to improved barrier repair and reduced oxidative stress.

**Full Content:**
The copper peptide GHK-Cu is unique among regenerative agents because its effects appear to be largely epigenetic. It does not merely stimulate a receptor; it modulates the expression of thousands of human genes.
                

                ### Reversing the Genetic Clock

                
                    Greenfield et al. (2018) utilized the Connectivity Map (a genomic database) to analyze the effect of GHK on gene expression. The findings were remarkable: GHK induces a gene expression signature that opposes aging. It suppresses genes involved in tissue destruction and inflammation while upregulating genes associated with tissue repair and antioxidant defense.
                

                
                    This explains why GHK-Cu is often described as pressing a "reset button" on cells, returning them to a more youthful metabolic state.
                

                ### Dermatological Applications

                
                    Pickart and Margolina (2018) reviewed GHK's role in skin biology. The peptide facilitates tight skin remodeling by balancing the breakdown of old collagen (via metalloproteinases) with the synthesis of new, organized collagen. 
                

                
                    - Barrier Repair: Restores the integrity of the skin barrier.

                    - Anti-Inflammatory: Reduces oxidative stress damage (free radicals).

                    - Wound Healing: Accelerates the closure of surgical wounds.

                

                ### Conclusion

                
                    GHK-Cu serves as a master regulator of tissue health, bridging the gap between simple nutrition (copper transport) and complex genetic regulation.
                

                #### Sources

                
                    - Greenfield J. et al. (2018). Regenerative Actions of GHK-Cu... Int J Mol Sci.

                    - Pickart L., Margolina A. (2018). GHK peptide as a natural modulator... Biomed Rep.

---

## Glossary of Research Terms

### Peptide Purity

An overview of how purity is defined, measured via HPLC/MS, and why >99% purity matters for research.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### How is Peptide Purity Achieved and Verified?

                
                    At Pure U.S. Peptides, we provide peptides that exceed 99% purity. Using state-of-the-art solution and solid phase peptide synthetic technology, Pure U.S. Peptides is able to offer the finest quality peptides and proteins fit for any research study or application. Peptide purity is achieved and verified through uncompromising manufacturing and production processes, quality control measures, and the implementation of both high-performance liquid chromatography and mass spectrometry analysis.
                

                
                    
                        #### HPLC Analysis

                        
                            High performance liquid chromatography, or HPLC, is a scientific technique used to separate, identify, and quantify each component in a mixture. It is a superior process that allows highly accurate peptide testing to be accomplished.
                        

                    
                    
                        #### Mass Spectrometry

                        
                            Mass spectrometry (MS) is a technique used to measure masses within a sample by ionizing chemical species and sorting the ions based on their mass to charge ratio. The results are plotted with the ion signal as a function of the mass to charge ratio.
                        

                    
                

                
                    Both methods are highly accurate peptide testing techniques and scientifically prove the purity and identity of peptides ordered from Pure U.S. Peptides. We take great pride in the quality of all of the products we manufacture, and we implement testing at all stages of peptide production at our peptide synthesis lab, verifying our peptides' sequential fingerprints for precision accuracy in every preparation.
                

                ### What is the Recommended Peptide Purity Level?

                
                    Pure U.S. Peptides provides only the highest purity peptides (>99% pure) for sale for research and development use. However, preparations of peptides synthesized for research by many other manufacturers can vary widely in purity. Occasionally, researchers can wonder what the minimum acceptable level of peptide purity is for their given purpose. Generally, the higher the peptide purity level, the more favorable the preparation; critically, for certain applications (such as in vitro studies or clinical trials), only exceedingly pure peptides will be appropriate (greater than 98% purity).
                

                
                    
                        
                            
                                Purity Level
                                Recommended Applications
                            
                        
                        
                            
                                Highly Pure (>95%)
                                
                                    
                                        - In vitro and in vivo studies

                                        - Clinical trials

                                        - Drug studies as pharmaceuticals

                                        - Cosmetic peptides

                                        - Crystallography & Antibody production

                                        - Quantitative ELISA and RIA protocol standard

                                    
                                
                            
                            
                                Mid-range (>85%)
                                
                                    
                                        - Peptide blocking studies (Western blot)

                                        - Phosphorylation studies

                                        - NMR studies

                                        - Cell attachment studies

                                        - Epitope mapping tests

                                    
                                
                            
                            
                                Lower Purity (>70%)
                                
                                    
                                        - Peptide arrays

                                        - Performing an ELISA standard for measuring titers

                                        - Antigens for polyclonal antibody production

                                    
                                
                            
                        
                    
                

                
                    Those peptides with greater purity are appropriate for use in an application with a lower minimum acceptable level of purity. Pure U.S. Peptides provides exceedingly high purity peptides that will meet or exceed all previously stated purity requirements.

---

### Intro to Peptides

A biologically occurring chemical compound containing two or more amino acids connected to one another by peptide bonds.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is a Peptide?

                
                    A peptide is a biologically occurring chemical compound containing two or more amino acids connected to one another by peptide bonds. A peptide bond is a covalent bond that is formed between two amino acids when a carboxyl group or C-terminus of one amino acid reacts with the amino group or N-terminus of another amino acid in a condensation reaction (a molecule of water is released during the reaction).
                

                
                     The resulting bond is a CO-NH bond and forms a peptide, or amide molecule. Likewise, peptide bonds are amide bonds.
                

                
                    The word "peptide" itself comes from πέσσειν, the Greek word meaning "to digest." Peptides are an essential part of nature and biochemistry, and thousands of peptides occur naturally in the human body and in animals. In addition, new peptides are being discovered and synthesized regularly in the laboratory as well. Indeed, this discovery and innovation in the study of peptides holds great promise for the future in the fields of health and pharmaceutical development.
                

                ### How Are Peptides Formed?

                
                    Peptides are formed both naturally within the body and synthetically in the laboratory. The body manufactures some peptides organically, such as ribosomal and non-ribosomal peptides. In the laboratory, modern peptide synthesis processes can create a virtually boundless number of peptides using peptide synthesis techniques like liquid phase peptide synthesis or solid phase peptide synthesis. While liquid phase peptide synthesis has some advantages, solid phase peptide synthesis is the standard peptide synthesis process used today.
                

                
                    Historical Milestone

                    
                        The first synthetic peptide was discovered in 1901 by Emil Fischer in collaboration with Ernest Fourneau. Oxytocin, the first polypeptide, was synthesized in 1953 by Vincent du Vigneaud.
                    

                

                ### Peptide Terminology

                
                    Peptides are generally classified according to the amount of amino acids contained within them.
                

                
                    - Dipeptide: A peptide composed of just two amino acids.

                    - Tripeptide: A peptide composed of three amino acids.

                    - Oligopeptides: Shorter peptides made up of relatively small numbers of amino acids, generally less than ten.

                    - Polypeptides: Typically composed of more than at least ten amino acids.

                    - Proteins: Much larger peptides (those composed of more than 40-50 amino acids).

                
                
                    While the number of amino acids contained is a main determinate when it comes to differentiating between peptides and proteins, exceptions are sometimes made. For example, certain longer peptides have been considered proteins (like amyloid beta), and certain smaller proteins are referred to as peptides in some cases (such as insulin).
                

                ### Classification of Peptides

                
                    Peptides are generally divided into several classes based on how they are produced:
                

                
                    - 
                        Ribosomal Peptides: Produced from the translation of mRNA. They often function as hormones and signaling molecules (e.g., substance P, vasoactive intestinal peptide). They frequently undergo proteolysis to reach their mature form.
                    

                    - 
                        Nonribosomal Peptides: Produced by peptide-specific enzymes, not the ribosome. These are frequently cyclic rather than linear and often appear in plants, fungi, and single-celled organisms. Glutathione is a common example.
                    

                    - 
                        Milk Peptides: Formed from milk proteins via enzymatic breakdown by digestive enzymes or lactobacilli fermentation.
                    

                    - 
                        Peptones: Derived from animal milk or meat digested by proteolytic enzymes, often used as nutrients for growing bacteria in labs.
                    

                

                ### Important Peptide Terms

                
                    
                        #### Amino Acids

                        Peptides are composed of amino acids. An amino acid is any molecule that contains both amine and carboxyl functional groups.

                    
                    
                        #### Cyclic Peptides

                        A peptide in which the amino acid sequence forms a ring structure instead of a straight chain (e.g., Melanotan-2, PT-141).

                    
                    
                        #### Peptide Bond

                        A covalent bond formed between two amino acids when a carboxyl group reacts with an amino group, releasing water (condensation).

                    
                    
                        #### Peptide Mimetics

                        A molecule that biologically mimics active ligands of hormones, cytokines, or other bio-molecules.

---

### Peptide Synthesis

A breakdown of the solid-phase synthesis (SPPS) process, protecting groups like Fmoc/Boc, and purification.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Peptide Synthesis?

                
                    Characterized by the formation of a peptide bond between two amino acids, peptide synthesis is, essentially, the production of peptides. Though peptide synthesis was somewhat hampered by relatively inefficient production practices at its inception, advancements in chemistry and technology have led to vastly improved synthesis methods. With the strong growth of the field of peptide science, it is clear that synthetic peptides will continue to play vital roles in areas of scientific and medical progress in the modern age.
                

                ### How Peptides are Synthesized

                
                    Peptides are synthesized by linking two amino acids together. This is most often accomplished by attaching the C-terminus, or carboxyl group, of one amino acid to the N-terminus, or amino group, of another. Unlike protein biosynthesis, which involves N-terminus to C-terminus linkage, peptide synthesis occurs in this C-to-N fashion.
                

                
                    While there are twenty amino acids that occur commonly in the natural world (such as arginine, lysine, and glutamine), many other amino acids have also been synthesized. This allows for abundant possibilities in the creation of new peptides. However, amino acids have numerous reactive groups that can negatively interact during the synthesis process, leading to unwanted truncating or branching of the peptide chain or causing suboptimal purity or yield. As a result, peptide synthesis is a complex process that must be expertly carried out.
                

                ### Protecting Groups

                
                    In order to ensure the desired outcome from the synthesis process and avoid extraneous, unwelcome reactions, certain amino acid reactive groups must be deactivated, or protected, from reacting. Thus, scientists have engineered special chemical groups designed to do just that.
                

                
                     
                        #### N-terminal Protecting Groups

                        These groups protect the N-termini of amino acids. Referred to as temporary protecting groups, they are removed relatively easily to facilitate the formation of peptide bonds. Tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) are two frequently used N-terminal protecting groups.

                     
                     
                        #### C-terminal Protecting Groups

                        These groups protect the C-terminus of amino acids. The use of C-terminal protecting groups is warranted in liquid-phase peptide synthesis but not solid-phase peptide synthesis.

                     
                     
                        #### Side Chain Protecting Groups

                        As amino acid side chains are quite conducive to reactivity during peptide synthesis, various unique side chain protecting groups are needed to protect against unwanted reactions. Known as permanent protecting groups, they are only removed with strong acids after synthesis concludes.

                     
                

                ### Peptide Synthesis Processes (SPPS)

                
                    The original approach to peptide synthesis was through a process known as solution phase synthesis (SPS). While SPS does have some merit today, notably in large-scale peptide production, it has largely been supplanted by solid-phase peptide synthesis, or SPPS. This is because SPPS offers several advantages, including high yield, purity, and speed of production.
                

                
                    SPPS involves five cyclical steps:

                    
                        - Attaching an amino acid to the polymer

                        - Protection (to prevent unwanted reactions)

                        - Coupling

                        - Deprotection (to allow the attached acid to react to the next amino acid)

                        - Polymer removal (resulting in a free peptide)

                    
                

                ### Purification and Value

                
                    While peptide synthesis processes like SPPS offer excellent purity and yield standards, impurities can still occur. This likelihood increases with the length of the peptide sequence. Therefore, purification techniques like Reverse-Phase Chromatography (RPC) and High-Performance Liquid Chromatography (HPLC) are utilized to separate impurities from the desired peptide.
                

                
                    Peptides have proven to be critical elements of biomedical research, and peptide synthesis continues to fuel scientific progress worldwide. The efficacy, specificity, and low toxicity of peptides assures us that peptides will continue to be pursued and developed for pharmaceutical and diagnostic purposes.

---

### Peptide Solubility

Understanding how to dissolve lyophilized peptides.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Peptide Solubility?

                
                    Peptide solubility refers to the ability of a peptide to dissolve in a given solvent, most commonly water or aqueous buffers. Since most research peptides are supplied in a lyophilized (freeze-dried) powder form, understanding how to properly dissolve them is essential for preparing accurate experimental solutions. The solubility of a peptide is primarily determined by its amino acid composition, overall charge, sequence length, and the polarity of its side chains.
                

                ### Determining Solubility Based on Amino Acid Composition

                
                    A peptide's solubility can generally be predicted by examining the proportion of hydrophobic versus hydrophilic residues in its sequence. Peptides containing a high percentage of charged or polar amino acids (such as Arg, Lys, Asp, Glu, His, Asn, and Gln) tend to be readily soluble in aqueous solutions. Conversely, peptides rich in hydrophobic residues (such as Ala, Val, Ile, Leu, Phe, Trp, and Met) may require the addition of organic co-solvents to achieve dissolution.
                

                
                    #### General Guidelines

                    
                        - Acidic peptides (net negative charge): Dissolve in basic solvents or add a small amount of dilute ammonium hydroxide (NH4OH).

                        - Basic peptides (net positive charge): Dissolve in acidic solvents or add a small amount of dilute acetic acid (up to 10%).

                        - Neutral or hydrophobic peptides: May require organic solvents such as DMSO, DMF, or acetonitrile, followed by dilution with water or buffer.

                    
                

                ### Best Practices for Dissolving Lyophilized Peptides

                
                    When preparing peptide solutions for research, it is important to follow a methodical approach to avoid irreversible aggregation or degradation. Always begin by dissolving a small test amount of the peptide before committing the entire sample. Use sterile solvents and containers to prevent contamination.
                

                
                    - Start with a small aliquot to test solubility before dissolving the full amount.

                    - Use sterile, deionized water or appropriate buffer as the primary solvent.

                    - If the peptide does not dissolve in water, add a small volume of DMSO first, then dilute with aqueous buffer.

                    - Avoid vigorous vortexing, as this can cause foaming and peptide denaturation; gentle sonication is preferred.

                    - Once dissolved, aliquot the solution and store appropriately to avoid repeated freeze-thaw cycles.

                

                ### Common Solvents Used in Peptide Research

                
                    
                        #### Sterile Water

                        The preferred first-choice solvent for most hydrophilic and charged peptides.

                    
                    
                        #### DMSO

                        A versatile organic solvent effective for hydrophobic peptides. Typically used at minimal volumes before aqueous dilution.

                    
                    
                        #### Acetic Acid (dilute)

                        Useful for dissolving basic peptides that carry a net positive charge at neutral pH.

                    
                    
                        #### Ammonium Hydroxide (dilute)

                        Appropriate for acidic peptides that carry a net negative charge at neutral pH.

---

### Peptide Purification

A detailed look at purification strategies like HPLC, Ion Exchange, and Reverse Phase Chromatography.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                
                    In the modern era, huge leaps forward in the scientific field of peptide synthesis have enabled the production of custom peptides on an immense scale. With the increased production of synthetic peptides for research, the implementation of effective peptide purification methods has only become more critical. For more information on how Pure U.S. Peptides ensures that every peptide on our website exceeds 99% purity, see our Peptide Purity page.
                

                
                    Peptides are complex molecules, and this complexity can render purification methods that are effective on other organic compounds inefficient. During synthesis, special attention must be paid to maximizing both efficiency and yield in order to provide customers with the purest possible peptide at the lowest possible price. While purification processes based on crystallization are often effective with other compounds, many peptide purification processes utilize the principles of chromatography, such as high-pressure reversed phase chromatography.
                

                ### Removing Specific Impurities From Peptides

                
                    As mentioned before, it is vital that the final synthesized peptide is as pure as possible for research use. Minimum acceptable purity levels can vary among different research purposes; for example, in vitro studies generally require a much higher standard of purity (greater than 95%) than, say, performing an ELISA standard for measuring titers of antibodies (minimum acceptable purity greater than 70%).
                

                
                    Common Impurities: Hydrolysis products of labile amide bonds, deletion sequences (SPPS), diastereomers, insertion peptides, and by-products formed during removal of protection groups.
                

                ### Peptide Purification Strategy

                
                    Ideally, the purification method should be as simple as possible, achieving targeted purity in as few steps as possible. Often, two or more purification processes conducted sequentially can give excellent results, particularly when each process operates through differing principles of chromatography.
                

                ### Peptide Purification Processes

                
                    Peptide purification systems are composed of several integral subsystems and units, which can include buffer preparation systems, solvent delivery systems, fractionation systems, and data collection systems, along with the crucial columns and detectors. Indeed, the column is the heart of the purification system and its selected features can be critical to the process's efficaciousness.
                

                
                    
                        #### Affinity Chromatography (AC)

                        
                            Isolates peptides by capitalizing on the interaction between a peptide and a particular ligand attached to a chromatographic matrix. The desired peptide binds to the ligand, and unbound material is washed away. Importanly, this binding is reversible.
                        

                    

                    
                        #### Ion Exchange Chromatography (IEX)

                        
                            Capitalizes on differences in charge among peptides in a mixture. Peptides of one charge are isolated when faced with a chromatographic medium with the opposite charge. IEX is a high resolution and high capacity process.
                        

                    

                    
                        #### Hydrophobic Interaction Chromatography (HIC)

                        
                            Operates on the principle of hydrophobicity. Targeted peptides are isolated via interaction with the hydrophobic surface of a chromatic medium. A high ionic strength buffer enhances the process.
                        

                    

                    
                        #### Reversed Phase Chromatography (RPC)

                        
                            Offers very high resolution and separates peptides from contaminants by utilizing the reversible interaction between target molecules and a chromatographic medium's hydrophobic surface. RPC is often utilized as a polishing step.
                        

                    
                

                ### Compliance with GMP

                
                    Throughout the processes of peptide synthesis and purification, special attention must be given to following GMP (Good Manufacturing Practices). This is to ensure that the final peptide is pure and of high quality. At Pure U.S. Peptides, we adhere to the most stringent synthesis and purification practices in the industry, allowing us to provide peptides that exceed 99% purity.

---

### Peptide Bonds

A covalent chemical bond linking two consecutive amino acid monomers along a peptide or protein chain.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is a Peptide Bond?

                
                    A peptide bond is a covalent bond that is formed between two amino acids. To form a peptide bond, a carboxyl group of one amino acid reacts with the amino group of another amino acid. As a result, a molecule of water is also released. This is referred to as a condensation reaction. The resulting bond is a CO-NH bond and is henceforth referred to as a peptide bond. Additionally, the resulting molecule is termed an amide.
                

                ### Peptide Bond Formation

                
                    In order to form a peptide bond, the molecules of the amino acids in question must be orientated so that the carboxylic acid group of one amino acid is able to react with the amine group of another amino acid. At its most basic, this can be illustrated by two lone amino acids combining through the formation of a peptide bond to form a dipeptide, the smallest peptide (i.e. only composed of 2 amino acids).
                

                
                    Any number of amino acids can be joined together in chains to form new peptides: as a general guideline, 50 or less amino acids are referred to as peptides, 50 – 100 are termed polypeptides, and peptides with over 100 amino acids are generally referred to as proteins.
                
                
                    Hydrolysis (a chemical breakdown of a compound resulting from a reaction with water) can break down a peptide bond. Though the reaction itself is quite slow, the peptide bonds formed within peptides, polypeptides, and proteins are susceptible to breakage when they come into contact with water (metastable bonds).
                

                
                    - Energy Release: The reaction between a peptide bond and water releases about 10kJ/mol of free energy.

                    - Absorbance: The wavelength of absorbance for a peptide bond is 190-230 nm.

                

                ### Structure of the Peptide Bond

                
                    Scientists have conducted x-ray diffraction studies of several small peptides to ascertain the physical characteristics of peptide bonds. Such studies have indicated that peptide bonds are rigid and planar. These physical characteristics are principally derived as a result of the resonance interaction of the amide: the amide nitrogen is able to delocalize its sole pair of electrons into the carbonyl oxygen.
                

                
                    This resonance directly affects the structure of the peptide bond. Indeed, the N–C bond of the peptide bond is actually shorter than the N–Cα bond, and the C=O bond is longer than normal carbonyl bonds. In the peptide, the carbonyl oxygen and amide hydrogen are in a trans configuration, not a cis configuration; such a configuration is more energetically favorable due to the possibility of steric interactions in a cis configuration.
                

                ### The Polarity of the Peptide Bond

                 
                    Usually, free rotation should be able to take place about a single bond between a carbonyl carbon and amide nitrogen, the structure of a peptide bond. However, the nitrogen in this case has a lone pair of electrons. These electrons are near a carbon-oxygen bond. As a result, a reasonable resonance structure can be drawn, in which a double bond links the carbon and nitrogen.
                

                
                    Consequently, the oxygen has a negative charge and the nitrogen has a positive charge. Rotation around the peptide bond is therefore inhibited by the resonance structure.
                

                
                    
                        -0.28
                        Oxygen Charge
                    
                     
                        +0.28
                         Nitrogen Charge

---

### Peptide Storage

Best practices for storing lyophilized and reconstituted peptides to ensure long-term stability.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### Best Practices For Storing Peptides

                
                    To preserve the integrity of laboratory results, proper storage of peptides is essential. Correct storage practices can maintain peptides for years and guard against contamination, oxidation, and degradation that may render your peptides, and therefore experiments, useless. While some peptides are more susceptible to degradation than others, knowing and implementing the best practices for peptide storage can greatly lengthen their stability and integrity regardless of composition.
                

                
                    
                        #### Short-Term Storage

                        
                            If the peptides will be used immediately, or in the next several days, weeks or months, short-term refrigeration under 4C (39F) is generally acceptable. Lyophilized peptides are usually stable at room temperatures for several weeks.
                        

                    
                    
                        #### Long-Term Storage

                        
                            For longer term storage (several months to years) it is more preferable to store peptides in a freezer at -80C (-112F). When storing peptides for months or even years, freezing is optimal in order to preserve the peptide's stability.
                        

                    
                

                
                    Note: Avoid repeated freeze-thaw cycles. This can increase the peptide's susceptibility to degradation. Also, frost-free freezers should be avoided to store peptides, as temperatures can fluctuate widely during defrosting cycles.
                

                ### Preventing Oxidation and Moisture Contamination

                
                    It is imperative to avoid contaminating peptides with both air and moisture. Moisture contamination is especially prone to occur when using a peptide immediately after withdrawing it from the freezer. To prevent uptake of moisture from the air on the cold surface of the peptide or on the inside of its container, allow the peptide to come to room temperature before opening.
                

                
                    It is also crucially important to minimize a peptide's exposure to the air. After the required amount of peptide has been removed, resealing the container under an atmosphere of dry, inert gas (such as nitrogen or argon) will minimize the potential for the remaining peptide to become oxidized.
                

                ### Storing Peptides In Solution

                
                    The shelf life of peptide solutions is far less than that of lyophilized peptides, and peptides stored in solution are also vulnerable to bacterial degradation. Peptides containing Cys, Met, Trp, Asp, Gln, and N-terminal Glu in their sequences have especially short shelf lives when in solution.
                

                
                    Nevertheless, if peptides absolutely must be stored in solution, sterile buffers at pH 5-6 should be used. Peptide solutions are generally stable for up to 30 days when refrigerated at 4C (39F), but those peptides with inherent instability should be kept frozen when not in use.
                

                 ### Summary Checklist

                
                    - Store peptide in a cold, dry, dark place.

                    - Avoid repeated freezing and thawing of peptide.

                    - Avoid overexposure to the air and light.

                    - Avoid storing peptides in solution long term.

                    - Aliquot peptide into separate vials according to experimental requirements.

---

### Research Peptides

Legal and safety guidelines for research use.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What Are Research Peptides?

                
                    Research peptides are synthetic peptides manufactured specifically for use in scientific and laboratory investigations. They are not intended for human consumption, therapeutic use, or any form of bodily introduction. Instead, research peptides serve as essential tools for scientists studying biological mechanisms, cellular signaling, receptor binding, and a wide range of other biochemical processes. These compounds are synthesized to exacting purity standards and are accompanied by documentation such as Certificates of Analysis (COA) and HPLC/MS data to verify their identity and composition.
                

                ### Legal Framework and Compliance

                
                    Research peptides occupy a specific regulatory space. In the United States, they are legal to purchase, possess, and use for legitimate research purposes. However, they are not approved by the FDA for human use, and selling them as dietary supplements, drugs, or for human consumption is prohibited. Reputable suppliers clearly label their products as "For Research Use Only" and require purchasers to acknowledge that the peptides will be used exclusively for in-vitro or authorized laboratory studies.
                

                
                    Researchers and institutions should be aware of their jurisdiction's specific regulations regarding the procurement, handling, and disposal of research chemicals. Maintaining proper documentation and following institutional review board (IRB) guidelines, where applicable, is essential for compliance.
                

                ### Safety Guidelines for Handling Research Peptides

                
                    Although research peptides are generally considered safe when handled properly in a laboratory setting, standard laboratory safety practices should always be followed. This includes wearing appropriate personal protective equipment (PPE) such as gloves, lab coats, and eye protection. Peptides should be stored according to manufacturer recommendations, typically in a cool, dry environment away from light and moisture to maintain stability and prevent degradation.
                

                
                    - Always handle peptides in a clean, well-ventilated laboratory environment.

                    - Wear gloves and appropriate PPE when handling lyophilized or reconstituted peptides.

                    - Follow the supplier's storage and reconstitution instructions precisely.

                    - Dispose of unused peptides and contaminated materials according to institutional and local waste disposal regulations.

                    - Maintain accurate records of peptide procurement, usage, and disposal for compliance and reproducibility.

                

                ### Choosing a Reliable Peptide Supplier

                
                    The quality of research peptides can vary significantly between suppliers. When selecting a source, researchers should look for manufacturers that provide third-party tested Certificates of Analysis, utilize validated HPLC and mass spectrometry testing methods, and maintain transparent quality control processes. Pure U.S. Peptides manufactures all peptides domestically and provides full analytical documentation with every order, ensuring that researchers receive compounds exceeding 99% purity for dependable, reproducible results.

---

### Peptides vs Proteins

The key differences defined by chain length and three-dimensional folding.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What are the Differences?

                
                    Peptides and proteins, while similar in many regards, have several key differences that are important to understand. Oftentimes the terms "peptide" and "protein" are used synonymously, but differing characteristics and biological activities between the two compounds prevent the terms from being totally interchangeable. To fully appreciate the differences between proteins and peptides, it is important to understand amino acids, the building blocks of both, and how all three (amino acids, peptides, and proteins) relate to one another.
                

                
                     
                        #### Peptides

                        
                            Short chains of amino acids linked by peptide bonds. Generally refers to a compound made up of two or more amino acids (e.g., Dipeptide, Tripeptide). Further classified as Oligopeptides (few, typically Polypeptides (>10).
                        

                     
                     
                        #### Proteins

                        
                             Historically defined as polypeptides composed of more than 50 amino acids. Crucially, proteins fold into stable, fixed three-dimensional structures required for specific biological functions (e.g., hemoglobin).
                        

                     
                

                ### Amino Acids: The Building Blocks

                
                    Amino acids are small but biologically vital compounds containing an amino group (NH2) and a carboxylic acid group (COOH) as well as a side-chain structure that varies between different amino acids. While hundreds of amino acids are known, only twenty are genetically combined into peptides (such as arginine, lysine, and glutamine), while others can be combined synthetically.
                

                
                    Importantly, amino acids make up the building blocks of peptides. When amine and carboxylic acid functional groups in amino acids join to form amide bonds, a peptide is formed.
                

                ### Key Distinctions: Size and Structure

                
                    
                        Scientists commonly differentiate between proteins and polypeptides based on two main factors:
                    

                    
                         - 
                            Size: A polypeptide composed of more than 50 amino acids is generally classified as a protein, though the threshold can range from 40-100 amino acids.
                         

                         - 
                            Structure: Typically, polypeptides shorter than about 40-50 amino acids in length do not fold into a fixed structure. Proteins, however, form stable 3D structures.
                         

                    
                

                ### Which Term to Use?

                
                    Importantly, all proteins are technically polypeptides. However, as a researcher, it can sometimes be useful to differentiate between the two and reserve the term "proteins" to refer to relatively long and structurally fixed amino acid chains. Accordingly, peptides will generally refer to shorter (sub-50) amino acid chains.

---

### HPLC (High-Performance Liquid Chromatography)

A powerful analytical technique used to separate, identify, and quantify components in peptide mixtures with exceptional precision.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is HPLC?

                
                    High-Performance Liquid Chromatography (HPLC) is an advanced analytical chemistry technique used to separate, identify, and quantify each component within a liquid mixture. In the context of peptide science, HPLC is the gold-standard method for determining peptide purity. The technique works by pumping a sample dissolved in a solvent (the mobile phase) at high pressure through a column packed with a solid adsorbent material (the stationary phase). Different components in the mixture interact with the stationary phase at different rates, causing them to elute from the column at different times, thereby achieving separation.
                

                ### How HPLC Works in Peptide Analysis

                
                    For peptide analysis, reversed-phase HPLC (RP-HPLC) is the most commonly employed variant. In RP-HPLC, the stationary phase is hydrophobic (typically C18-bonded silica), while the mobile phase is a polar aqueous-organic solvent mixture. Peptides are separated based on their hydrophobicity: more hydrophilic peptides elute first, while more hydrophobic peptides are retained longer on the column. A UV detector, typically set at 214 nm (the absorbance wavelength of the peptide bond), monitors the eluting fractions. The resulting chromatogram displays peaks corresponding to each component, and the area under the main peak relative to total peak area provides the purity percentage.
                

                ### Why HPLC Matters for Research Peptides

                
                    HPLC analysis is essential for ensuring that research peptides meet the stringent purity requirements necessary for reliable experimental results. Without HPLC verification, researchers cannot be confident that their peptide preparations are free from synthesis by-products, deletion sequences, or other contaminants that could confound study outcomes. At Pure U.S. Peptides, every product undergoes rigorous HPLC testing, and the resulting chromatograms are included in the Certificate of Analysis provided with each order. This transparency allows researchers to verify that their peptides exceed 99% purity before beginning their experiments.
                

                ### Key HPLC Parameters

                
                    
                        #### Retention Time

                        The time a compound takes to travel through the column. Each peptide has a characteristic retention time under given conditions.

                    
                    
                        #### Resolution

                        The degree of separation between two adjacent peaks. Higher resolution means better distinction between the target peptide and impurities.

                    
                    
                        #### Mobile Phase Gradient

                        The programmed change in solvent composition over time, optimized to achieve the best separation for a given peptide mixture.

                    
                    
                        #### Detection Wavelength

                        Typically 214 nm or 220 nm for peptides, corresponding to the absorbance of the amide bond present in all peptides.

---

### Mass Spectrometry

An analytical technique that measures the mass-to-charge ratio of ions to confirm peptide identity and molecular weight.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Mass Spectrometry?

                
                    Mass spectrometry (MS) is an analytical technique that measures the mass-to-charge ratio (m/z) of ions within a sample. In peptide research, mass spectrometry is used alongside HPLC to confirm the molecular identity of synthesized peptides. The process involves three fundamental steps: ionization of the sample molecules, separation of the resulting ions based on their mass-to-charge ratios, and detection of those ions to produce a mass spectrum. The spectrum serves as a molecular fingerprint, enabling researchers to confirm that the synthesized peptide matches the intended sequence and molecular weight.
                

                ### Common MS Techniques in Peptide Analysis

                
                    Several ionization methods are commonly used for peptide analysis. Electrospray ionization (ESI) is widely employed because it can handle a broad range of peptide sizes and is easily coupled with HPLC systems (LC-MS). Matrix-assisted laser desorption/ionization (MALDI) is another popular technique, particularly useful for analyzing larger peptides and proteins. In MALDI, the sample is embedded in a crystalline matrix and ionized by a laser pulse. Both methods produce multiply charged ions that can be analyzed by time-of-flight (TOF), quadrupole, or ion trap mass analyzers.
                

                ### Interpreting Mass Spectrometry Data

                
                    The primary output of a mass spectrometry analysis is the mass spectrum, a plot of ion signal intensity versus mass-to-charge ratio. For peptide quality control, the observed molecular weight is compared against the theoretical molecular weight calculated from the peptide's amino acid sequence. A match within acceptable tolerance (typically less than 0.1% deviation) confirms the peptide's identity. Mass spectrometry can also reveal the presence of modifications, truncations, or impurities that might not be apparent from HPLC analysis alone, making it an indispensable complementary technique.
                

                ### MS and Quality Assurance

                
                    At Pure U.S. Peptides, mass spectrometry data is included in every Certificate of Analysis alongside HPLC results. Together, these two analytical methods provide a comprehensive quality profile: HPLC confirms purity, while MS confirms identity. This dual-verification approach ensures that researchers receive exactly the peptide they ordered, at the purity level they require for rigorous, reproducible experimentation.

---

### GMP (Good Manufacturing Practices)

A system of quality assurance guidelines ensuring that products are consistently manufactured and controlled to appropriate standards.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is GMP?

                
                    Good Manufacturing Practices (GMP) are a set of regulatory guidelines and quality assurance principles designed to ensure that products are consistently produced and controlled according to established quality standards. Originally developed for the pharmaceutical and food industries, GMP principles have become the benchmark for peptide manufacturing as well. GMP covers all aspects of production, from raw materials and facility design to staff training, equipment calibration, documentation, and final product testing. Adhering to GMP helps minimize the risks of contamination, mix-ups, and errors that cannot be eliminated through testing the final product alone.
                

                ### Key Principles of GMP

                
                    - Documentation: Every step of the manufacturing process is recorded, creating a complete audit trail from raw materials to finished product.

                    - Facility and Equipment: Manufacturing environments must be clean, controlled, and regularly maintained. Equipment is calibrated and validated on a defined schedule.

                    - Personnel Training: All staff involved in production must be adequately trained in GMP principles and the specific procedures relevant to their roles.

                    - Quality Control: In-process testing and final product analysis (via HPLC, MS, and other methods) verify that each batch meets predetermined specifications.

                    - Standard Operating Procedures (SOPs): Detailed, written procedures govern every aspect of manufacturing, reducing variability and human error.

                

                ### GMP in Peptide Manufacturing

                
                    For research peptide suppliers, adhering to GMP principles translates to higher purity, more consistent batch-to-batch quality, and greater reliability for end users. While not all research-grade peptides are required to be manufactured under full cGMP (current Good Manufacturing Practices) conditions, reputable suppliers voluntarily adopt these standards to differentiate their products and build trust with the scientific community. At Pure U.S. Peptides, our commitment to GMP-aligned manufacturing processes is central to delivering peptides that consistently exceed 99% purity.

---

### ISO 17025

The international standard for the competence of testing and calibration laboratories, ensuring reliable analytical results.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is ISO 17025?

                
                    ISO/IEC 17025 is the international standard published by the International Organization for Standardization (ISO) that specifies the general requirements for the competence, impartiality, and consistent operation of testing and calibration laboratories. When a laboratory is accredited to ISO 17025, it means that its testing methods, equipment calibration procedures, and quality management systems have been independently evaluated and found to meet rigorous international benchmarks. For peptide research, this standard is particularly relevant to the laboratories that perform HPLC, mass spectrometry, and other analytical tests used to verify peptide purity and identity.
                

                ### Why ISO 17025 Matters for Peptide Quality

                
                    When a peptide supplier's analytical testing is performed by an ISO 17025-accredited laboratory, researchers can have greater confidence that the reported purity and identity data are accurate and reproducible. The standard requires laboratories to demonstrate technical competence in the specific tests they perform, maintain traceability of measurements to national or international standards, and participate in proficiency testing programs. This means that HPLC purity percentages and mass spectrometry molecular weight confirmations reported on a Certificate of Analysis carry the weight of internationally recognized validation.
                

                ### Key Requirements of ISO 17025

                
                    - Method Validation: Analytical methods must be validated or verified to confirm they are fit for their intended purpose.

                    - Measurement Uncertainty: Laboratories must estimate and report the uncertainty associated with their test results.

                    - Equipment Calibration: All instruments must be regularly calibrated using traceable reference standards.

                    - Quality Management: A comprehensive quality management system must be in place, including document control, internal audits, and corrective action procedures.

                

                ### ISO 17025 and Research Confidence

                
                    For researchers purchasing peptides, asking whether a supplier's testing laboratory holds ISO 17025 accreditation is a meaningful way to evaluate the reliability of purity and identity claims. Suppliers who invest in this level of quality assurance demonstrate a commitment to accuracy that directly benefits the reproducibility and credibility of downstream research findings.

---

### Lyophilization (Freeze-Drying)

The freeze-drying process used to preserve peptides in a stable, dry powder form for long-term storage and shipping.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Lyophilization?

                
                    Lyophilization, commonly known as freeze-drying, is a dehydration process used to preserve peptides and other biological materials by removing water from a frozen sample through sublimation (the direct transition from solid ice to water vapor without passing through the liquid phase). The result is a stable, dry powder that retains the chemical integrity and biological activity of the original peptide. Virtually all research peptides are supplied in lyophilized form because this state offers superior long-term stability compared to liquid solutions.
                

                ### The Lyophilization Process

                
                    The freeze-drying process occurs in three main stages. First, during the freezing stage, the peptide solution is cooled to a temperature well below its freezing point, forming ice crystals. Second, during primary drying (sublimation), the pressure is reduced and gentle heat is applied, causing the ice to sublimate directly into vapor, which is then collected by a condenser. Third, during secondary drying (desorption), residual bound water molecules are removed by raising the temperature further under vacuum. The result is a dry cake or powder with a moisture content typically below 1-3%.
                

                ### Benefits for Peptide Stability

                
                    Lyophilization is the preferred preservation method for peptides because it dramatically extends shelf life by eliminating the water that would otherwise promote hydrolysis, oxidation, and microbial growth. Lyophilized peptides can remain stable for years when stored properly at low temperatures (-20C or below), whereas peptides in solution may degrade within days or weeks. The process also facilitates accurate weighing, shipping at ambient temperature for short durations, and straightforward reconstitution when the researcher is ready to begin their experiments.
                

                ### Reconstituting Lyophilized Peptides

                
                    Before use in research, lyophilized peptides must be reconstituted by dissolving the powder in an appropriate solvent. The choice of solvent depends on the peptide's charge and hydrophobicity. Sterile water or bacteriostatic water is suitable for most hydrophilic peptides, while hydrophobic peptides may require a small amount of DMSO or dilute acetic acid. It is always advisable to dissolve a small test quantity first, and to consult the supplier's solubility recommendations provided with each product.

---

### Certificate of Analysis (COA)

An official document from the manufacturer that reports the analytical testing results and quality specifications for a peptide batch.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is a Certificate of Analysis?

                
                    A Certificate of Analysis (COA) is an official document issued by the peptide manufacturer that accompanies each batch of product and provides detailed analytical data confirming the peptide's identity, purity, and quality. The COA serves as verifiable proof that the peptide has been tested using validated analytical methods and meets or exceeds the stated specifications. For researchers, reviewing the COA before beginning experiments is an essential step in ensuring that their peptide reagents are suitable for the intended application.
                

                ### What Information Does a COA Contain?

                
                    
                        - Product Name and Catalog Number: Identifies the specific peptide and batch.

                        - Batch/Lot Number: A unique identifier for traceability.

                        - Amino Acid Sequence: The full sequence of the peptide, confirming its identity.

                        - Molecular Weight: Both theoretical and observed (via mass spectrometry).

                        - HPLC Purity: The percentage purity determined by high-performance liquid chromatography, often with the chromatogram included.

                        - Mass Spectrometry Data: The observed mass confirming the molecular identity.

                        - Appearance: Physical description of the lyophilized product (e.g., white powder).

                        - Storage Conditions: Recommended storage temperature and handling instructions.

                    
                

                ### Why the COA Matters for Research

                
                    The COA is a critical quality document that enables researchers to verify that their peptides are authentic, pure, and correctly manufactured before incorporating them into experiments. Without a COA, there is no independent verification that the peptide in the vial matches what was ordered. Reputable suppliers like Pure U.S. Peptides provide a comprehensive COA with every order, including raw HPLC chromatograms and mass spectrometry spectra, giving researchers full transparency into the quality of their reagents.

---

### In Vitro Research

Scientific experiments performed outside a living organism, typically in test tubes, petri dishes, or controlled laboratory environments.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What Does "In Vitro" Mean?

                
                    The term "in vitro" is Latin for "in glass" and refers to scientific experiments and procedures that are conducted outside of a living organism, in a controlled artificial environment such as a test tube, petri dish, cell culture flask, or microplate. In vitro studies are a cornerstone of modern biological and biomedical research, allowing scientists to isolate specific variables, study molecular interactions, and screen compounds under precisely controlled conditions without the complexity of a whole living system.
                

                ### In Vitro Studies and Peptide Research

                
                    Research peptides sold by Pure U.S. Peptides are furnished exclusively for in vitro studies. In the context of peptide research, in vitro experiments might include studying how a peptide interacts with specific cell receptors in a cell culture system, evaluating peptide stability under various conditions, measuring binding affinities using surface plasmon resonance or ELISA assays, or assessing the effects of peptides on cultured cell lines. These studies provide valuable preliminary data about a peptide's potential mechanisms of action and properties without involving living subjects.
                

                ### Advantages of In Vitro Research

                
                    - Control: Researchers can precisely control experimental variables such as temperature, pH, concentration, and exposure time.

                    - Reproducibility: Standardized conditions make it easier to replicate experiments across different laboratories.

                    - Efficiency: In vitro assays are generally faster and less expensive than in vivo studies, enabling high-throughput screening.

                    - Ethical Considerations: In vitro methods reduce the need for animal models in early-stage research.

                

                ### Limitations to Consider

                
                    While in vitro studies provide essential foundational data, they do not fully replicate the complexity of biological systems. Factors such as metabolism, immune response, tissue distribution, and organ-level interactions cannot be modeled in a dish. Therefore, in vitro results are typically considered preliminary and are often followed by additional studies to build a more complete understanding of a peptide's properties and behavior.

---

### In Vivo Research

Scientific experiments conducted within a living organism, providing data on biological responses in a whole-system context.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What Does "In Vivo" Mean?

                
                    The term "in vivo" is Latin for "within the living" and refers to experiments or observations that take place inside a living organism, such as an animal model. In vivo research is a critical stage in the scientific investigation of biological compounds, including peptides, because it reveals how substances behave within the full complexity of a living system, encompassing metabolism, immune responses, organ interactions, and systemic effects that cannot be replicated in a test tube or cell culture.
                

                ### In Vivo vs. In Vitro

                
                    While in vitro studies are conducted in controlled laboratory environments outside of living organisms, in vivo studies take place within whole organisms and therefore capture biological complexity that isolated cell-based experiments cannot. In a typical research pipeline, promising findings from in vitro experiments are advanced to in vivo models to evaluate pharmacokinetics (how a compound is absorbed, distributed, metabolized, and excreted), pharmacodynamics (the compound's effects on the organism), and safety profiles. Both approaches are complementary and necessary for thorough scientific investigation.
                

                ### Ethical and Regulatory Considerations

                
                    In vivo research involving animal models is governed by strict ethical guidelines and regulatory frameworks. In the United States, the Institutional Animal Care and Use Committee (IACUC) oversees the ethical review and approval of all animal research protocols. The guiding principle of the "3Rs" (Replacement, Reduction, and Refinement) seeks to minimize animal use by replacing animal models with alternatives where possible, reducing the number of animals used, and refining procedures to minimize discomfort. Research peptide suppliers, including Pure U.S. Peptides, provide products intended for lawful research conducted under appropriate institutional oversight and regulatory compliance.
                

                ### Peptide Purity Requirements for In Vivo Studies

                
                    In vivo studies demand exceptionally high purity peptides, generally exceeding 95%, to ensure that observed biological effects are attributable to the peptide itself and not to synthesis impurities. Contaminants such as residual solvents, truncated sequences, or endotoxins could introduce confounding variables or cause adverse effects. For this reason, researchers conducting in vivo studies should source their peptides from manufacturers that provide comprehensive Certificates of Analysis with verified HPLC and mass spectrometry data.

---

### Bioavailability

The proportion of a substance that enters circulation and is available to exert its biological effect when introduced into a living system.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Bioavailability?

                
                    Bioavailability is a pharmacokinetic term that describes the fraction of an administered substance that reaches systemic circulation in an unchanged, active form and is therefore available to produce a biological effect. In research contexts, bioavailability is a critical parameter for understanding how efficiently a peptide or other compound is absorbed and utilized by the biological system under study. A substance with 100% bioavailability (such as one administered directly into the bloodstream) is fully available, while substances administered by other routes may have significantly lower bioavailability due to processes like enzymatic degradation, poor absorption, or first-pass metabolism.
                

                ### Factors Affecting Peptide Bioavailability

                
                    Peptides present unique bioavailability challenges compared to small-molecule compounds. Their relatively large molecular size, susceptibility to enzymatic degradation by proteases, and often limited ability to cross biological membranes can all reduce bioavailability. Key factors that influence a peptide's bioavailability include:
                

                
                    - Route of Administration: Different administration routes (e.g., subcutaneous, intraperitoneal, oral) result in vastly different bioavailability profiles for peptides.

                    - Molecular Weight and Size: Larger peptides generally have more difficulty crossing biological membranes.

                    - Enzymatic Stability: Peptides are susceptible to degradation by proteolytic enzymes in the gastrointestinal tract, bloodstream, and tissues.

                    - Charge and Hydrophobicity: The physicochemical properties of a peptide's amino acid sequence influence membrane permeability and absorption rates.

                

                ### Improving Peptide Bioavailability in Research

                
                    Researchers employ several strategies to enhance peptide bioavailability in experimental settings. These include chemical modifications such as cyclization, N-methylation, or substitution with non-natural amino acids to improve protease resistance. Formulation approaches like encapsulation in nanoparticles or liposomes can also protect peptides from degradation and facilitate cellular uptake. Understanding and optimizing bioavailability is an active and important area of peptide research that directly impacts the translation of in vitro findings to meaningful in vivo observations.

---

### Half-Life

The time required for the concentration or activity of a peptide to decrease by half within a biological or experimental system.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Half-Life?

                
                    In the context of peptide research, half-life refers to the time required for the concentration or biological activity of a peptide to decrease by 50% within a given system. This can refer to the peptide's stability in solution (chemical half-life), its persistence in a biological system such as plasma or serum (biological half-life), or the duration of its biological effect (pharmacodynamic half-life). Half-life is a fundamental pharmacokinetic parameter that helps researchers understand how long a peptide remains active and at what dosing intervals it should be studied.
                

                ### Factors That Influence Peptide Half-Life

                
                    Natural peptides in biological systems typically have short half-lives, often ranging from just a few minutes to several hours. This is primarily due to rapid enzymatic degradation by proteases and peptidases present in plasma, tissues, and the gastrointestinal tract, as well as renal clearance. Several factors determine a specific peptide's half-life:
                

                
                    - Sequence Composition: Certain amino acid sequences are more resistant to proteolytic cleavage than others.

                    - Molecular Size: Smaller peptides are generally cleared more rapidly by the kidneys.

                    - Structural Modifications: Cyclization, PEGylation, lipidation, or D-amino acid substitution can extend half-life by improving protease resistance.

                    - Binding Interactions: Peptides that bind to serum proteins (such as albumin) may exhibit prolonged circulation times.

                

                ### In Vitro vs. In Vivo Half-Life

                
                    It is important to distinguish between in vitro and in vivo half-life measurements. In vitro half-life, measured in a controlled laboratory environment (such as stability in buffer or plasma at 37C), provides baseline data on a peptide's chemical and enzymatic stability. In vivo half-life, measured in a living system, reflects the combined effects of absorption, distribution, metabolism, and excretion (ADME). Researchers often begin with in vitro stability studies to guide the design of subsequent in vivo pharmacokinetic experiments.

---

### Molecular Weight

The sum of the atomic weights of all atoms in a peptide molecule, a critical value for identity confirmation and concentration calculations.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Molecular Weight?

                
                    Molecular weight (MW), also referred to as molecular mass, is the sum of the atomic weights of all atoms in a molecule, expressed in daltons (Da) or grams per mole (g/mol). For peptides, the molecular weight is calculated by summing the residue weights of each amino acid in the sequence, subtracting the water molecules lost during peptide bond formation, and accounting for any chemical modifications. Molecular weight is a fundamental physical property that is used to confirm a peptide's identity, calculate molar concentrations for experiments, and interpret mass spectrometry data.
                

                ### Calculating Peptide Molecular Weight

                
                    The molecular weight of a peptide can be calculated from its amino acid sequence using well-established atomic mass values. Each amino acid residue has a known average molecular weight (ranging from approximately 57 Da for glycine to 204 Da for tryptophan). The total molecular weight is determined by summing the residue masses and adding 18.02 Da for the water molecule at the terminal ends. Most research peptides have molecular weights ranging from a few hundred daltons (for di- and tripeptides) up to several thousand daltons (for longer sequences of 30-50 amino acids).
                

                ### Molecular Weight in Quality Control

                
                    In peptide quality control, the observed molecular weight obtained via mass spectrometry is compared to the theoretical molecular weight calculated from the intended sequence. Agreement between these values (typically within 0.1% or 1 Da) is strong confirmation that the correct peptide was synthesized. Discrepancies may indicate incomplete synthesis, deletion sequences, chemical modifications, or counterion effects. The molecular weight is always reported on the Certificate of Analysis alongside HPLC purity data.
                

                ### Practical Applications

                
                    Researchers rely on accurate molecular weight values for preparing solutions at precise molar concentrations, which is essential for dose-response studies, binding assays, and any experiment where stoichiometric relationships matter. The molecular weight is also important for selecting appropriate analytical methods, choosing chromatography columns, and interpreting pharmacokinetic data related to renal filtration and clearance.

---

### CAS Number

A unique numerical identifier assigned by the Chemical Abstracts Service to every chemical substance described in the scientific literature.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is a CAS Number?

                
                    A CAS (Chemical Abstracts Service) Registry Number is a unique numerical identifier assigned to every chemical substance described in the open scientific literature. Administered by the American Chemical Society's Chemical Abstracts Service division, CAS numbers serve as an unambiguous way to identify a specific chemical compound regardless of how many different names, synonyms, or naming conventions exist for it. For peptides, the CAS number provides a universal reference that links a specific peptide to its published research, safety data, and regulatory information across databases worldwide.
                

                ### CAS Number Format

                
                    CAS numbers are written as a series of digits separated by hyphens, in the format XXXXXXX-YY-Z. The first part can contain up to seven digits, the second part contains two digits, and the final single digit is a check digit used to verify the number's validity. For example, the CAS number for insulin is 11061-68-0, and for oxytocin it is 50-56-6. Each CAS number is unique to a single substance, meaning that different salt forms, stereoisomers, or modifications of the same base compound will each receive their own distinct CAS number.
                

                ### Why CAS Numbers Matter for Peptide Research

                
                    CAS numbers are invaluable tools for researchers working with peptides. They eliminate ambiguity when ordering, referencing, or searching for information about a specific compound. A peptide may be known by its generic name, brand names, abbreviations, or systematic IUPAC nomenclature, but the CAS number ensures that all parties are referring to exactly the same substance. When reviewing literature, checking regulatory status, or sourcing peptides from different suppliers, using the CAS number is the most reliable way to confirm compound identity.
                

                ### Finding CAS Numbers

                
                    CAS numbers for research peptides can be found on product pages, Certificates of Analysis, Safety Data Sheets (SDS), and in scientific databases such as PubChem, SciFinder, and the CAS Common Chemistry registry. Pure U.S. Peptides includes the CAS number on product listings where available, helping researchers cross-reference their purchases with published literature and regulatory databases efficiently.

---

### Amino Acid Sequence

The specific linear order of amino acid residues in a peptide chain, which determines its structure, function, and biological activity.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is an Amino Acid Sequence?

                
                    An amino acid sequence, also called the primary structure of a peptide or protein, is the specific linear order in which amino acid residues are connected by peptide bonds in a polypeptide chain. This sequence is conventionally written from the N-terminus (amino end) to the C-terminus (carboxyl end) and is typically represented using either the one-letter or three-letter amino acid codes. For example, the tripeptide glutathione is written as Glu-Cys-Gly (three-letter) or ECG (one-letter). The amino acid sequence is the most fundamental piece of information about a peptide, as it dictates the molecule's physical properties, three-dimensional folding, and biological function.
                

                ### How Sequence Determines Function

                
                    The specific arrangement of amino acids in a peptide's sequence determines virtually all of its properties. The sequence dictates the molecular weight, net charge at physiological pH, hydrophobicity, solubility, and susceptibility to enzymatic degradation. For longer peptides and proteins, the primary sequence also governs how the chain folds into secondary structures (alpha helices, beta sheets) and tertiary structures (the overall 3D shape), which in turn determine biological activity. Even a single amino acid substitution can dramatically alter a peptide's binding affinity, stability, or function.
                

                ### Sequence Notation Conventions

                
                    
                        #### Three-Letter Code

                        Uses abbreviations like Ala, Gly, Leu, Phe for each amino acid. Preferred for short peptides and when clarity is paramount (e.g., H-Ala-Gly-Cys-Lys-OH).

                    
                    
                        #### One-Letter Code

                        Uses single letters like A, G, L, F for each amino acid. Preferred for longer sequences due to compactness (e.g., AGCKL). Common in database entries and bioinformatics.

                    
                

                ### Sequence Verification in Quality Control

                
                    Confirming the correct amino acid sequence is a critical step in peptide quality control. Mass spectrometry is the primary method used to verify that the synthesized peptide matches the intended sequence. Tandem mass spectrometry (MS/MS) can fragment the peptide at peptide bonds, producing a series of fragment ions that allow the sequence to be read and confirmed. The amino acid sequence is always reported on the Certificate of Analysis and should be verified by the researcher before incorporating the peptide into any experimental protocol.

---

### Reconstitution

The process of dissolving a lyophilized peptide powder in an appropriate solvent to prepare it for use in research experiments.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What is Reconstitution?

                
                    Reconstitution is the process of dissolving a lyophilized (freeze-dried) peptide powder in an appropriate solvent to create a solution suitable for use in research experiments. Since most research peptides are supplied as lyophilized powders for optimal stability during storage and shipping, reconstitution is a necessary preparation step before any experimental application. Proper reconstitution technique is essential for maintaining peptide integrity, achieving accurate concentrations, and ensuring reliable experimental results.
                

                ### Step-by-Step Reconstitution Process

                
                    - Allow the vial to reach room temperature before opening to prevent moisture condensation on the cold peptide powder, which can cause degradation.

                    - Calculate the required volume of solvent based on the desired final concentration using the peptide's molecular weight and the amount of material in the vial.

                    - Add the solvent slowly along the inside wall of the vial rather than directly onto the peptide cake to avoid splashing or foaming.

                    - Allow the peptide to dissolve naturally. If needed, gently swirl the vial or use brief, gentle sonication. Avoid vigorous vortexing, which can denature certain peptides.

                    - Verify complete dissolution by visually inspecting the solution for clarity. A clear solution indicates complete dissolution.

                

                ### Choosing the Right Solvent

                
                    The choice of reconstitution solvent depends on the peptide's physicochemical properties. Sterile water or bacteriostatic water is appropriate for most hydrophilic peptides carrying charged residues. For hydrophobic peptides, a small volume of DMSO (typically 50-100 microliters) can be used as an initial solvent, followed by dilution with aqueous buffer to the desired concentration. Dilute acetic acid (0.1%) is suitable for basic peptides, while dilute ammonium hydroxide can be used for acidic peptides. Always consult the supplier's recommendations for specific reconstitution guidance.
                

                ### Post-Reconstitution Storage

                
                    Once reconstituted, peptide solutions are significantly less stable than their lyophilized counterparts. It is strongly recommended to aliquot the reconstituted peptide into single-use volumes immediately after preparation, then store the aliquots at -20C or below. This practice avoids the damaging effects of repeated freeze-thaw cycles. Reconstituted peptide solutions stored under refrigeration (2-8C) should ideally be used within a few days to a few weeks, depending on the specific peptide's stability profile.

---

### Endotoxin Testing

Analytical testing to detect and quantify bacterial endotoxins (lipopolysaccharides) that could compromise research results.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What Are Endotoxins?

                
                    Endotoxins are lipopolysaccharides (LPS) found in the outer membrane of Gram-negative bacteria. These molecules are released when bacterial cells die and disintegrate, and they are among the most potent biological contaminants encountered in laboratory settings. Even in trace quantities measured in endotoxin units (EU), endotoxins can trigger significant immune responses in biological systems, activate inflammatory pathways in cell cultures, and introduce confounding variables that compromise the validity of research results. For these reasons, endotoxin testing is a critical quality control measure for research peptides.
                

                ### The LAL Assay

                
                    The Limulus Amebocyte Lysate (LAL) assay is the most widely used method for detecting and quantifying endotoxins. This assay is based on a biological reaction discovered in the blood cells (amebocytes) of the horseshoe crab (Limulus polyphemus). When exposed to endotoxins, the lysate of these cells initiates a clotting cascade. Modern LAL assays use this reaction in quantitative formats, including gel-clot, turbidimetric (kinetic), and chromogenic methods, to measure endotoxin levels with high sensitivity, typically detecting concentrations as low as 0.01 EU/mL.
                

                ### Why Endotoxin Testing Matters for Peptide Research

                
                    Endotoxin contamination in research peptides can profoundly affect experimental outcomes, particularly in cell-based assays, immunological studies, and in vivo research. Even sub-nanogram quantities of endotoxin can activate macrophages, stimulate cytokine production, and alter cell proliferation rates, leading to false positives or masking true biological effects of the peptide under study. Researchers conducting in vivo studies must be especially vigilant, as endotoxins can cause fever, inflammation, and shock in animal models.
                

                ### Acceptable Endotoxin Levels

                
                    The acceptable endotoxin level depends on the intended application. For in vivo research, endotoxin levels should generally be below 5 EU per kilogram of body weight per hour for the test subject. For in vitro cell culture work, even lower levels may be required to prevent immune cell activation. High-quality peptide suppliers test each batch and report endotoxin levels on the Certificate of Analysis when applicable. Researchers should always verify that endotoxin levels meet the requirements of their specific experimental protocol before proceeding.

---

### Bioregulators

Short peptide sequences, typically 2-4 amino acids in length, studied for their ability to interact with DNA and influence gene expression.

#### Notice

                    
                        ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
                    

                

                ### What Are Bioregulators?

                
                    Bioregulators, also known as bioregulatory peptides or Khavinson peptides (named after Professor Vladimir Khavinson, who pioneered their research), are ultra-short peptide sequences typically composed of just 2 to 4 amino acids. These small peptides are studied for their ability to penetrate cell membranes, interact with specific DNA sequences, and modulate gene expression in a tissue-specific manner. Unlike larger peptides that typically act by binding to cell-surface receptors, bioregulators are hypothesized to work at the epigenetic level, influencing how genes are read and expressed within specific cell types.
                

                ### How Bioregulators Are Studied

                
                    Research into bioregulators focuses on their potential to interact with the promoter regions of specific genes. In vitro studies using cell culture models have examined how these short peptide sequences may influence protein synthesis, cell proliferation, and cellular differentiation. Due to their very small molecular weight (typically under 500 Da), bioregulators present interesting pharmacokinetic properties, including relatively high stability and the theoretical ability to cross cell membranes without specialized transport mechanisms. The field remains an active area of investigation, with ongoing studies exploring the specificity and mechanisms of these peptide-DNA interactions.
                

                ### Categories of Bioregulators

                
                    Bioregulators are often classified according to the tissues or organ systems they have been studied in relation to. Examples studied in the research literature include peptides investigated for their interactions with thymic tissue, pineal gland cells, vascular endothelium, retinal tissue, and various other organ-specific cell types. Each bioregulator is characterized by its unique amino acid sequence and the specific gene promoter regions it has been observed to interact with in experimental settings.
                

                ### Research Considerations

                
                    As with all research peptides, bioregulators available from Pure U.S. Peptides are intended exclusively for in vitro laboratory research. The quality and purity of bioregulatory peptides is especially important because their extremely short sequences mean that even minor impurities could represent a significant molar fraction of the total sample. All bioregulator peptides undergo the same rigorous HPLC and mass spectrometry testing as longer peptides, with complete analytical documentation provided in the Certificate of Analysis for each batch.

---

## Quality Assurance & Testing

Pure U.S. Peptides maintains the highest quality standards in the research peptide industry:

- **HPLC Testing**: High-Performance Liquid Chromatography on every batch, verifying 99%+ purity
- **Mass Spectrometry**: Molecular identity confirmation via MS analysis
- **Third-Party Testing**: Independent verification by ISO 17025 accredited laboratories
- **Certificate of Analysis**: COA available for every product batch
- **GMP Manufacturing**: All products manufactured under Good Manufacturing Practice conditions
- **USA-Based**: All testing and verification performed in United States laboratories

## Disclaimer

All products are intended for laboratory in-vitro research purposes only. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition. Bodily introduction of any kind into humans or animals is strictly forbidden by law.