VIP

Vasoactive Intestinal Peptide (VIP) is a 28-aminoacido signaling neuropeptide pertencente a the glucagon-secretin superfamily. [1] It is a highly conserved molecule across mammalian evolution, identical in humans, pigs, rats, and cows. VIP was originalmente isolado(a) de the porcine duodenum by Sami I. Said and Viktor Mutt in 1970 no(a) Medical College of Virginia and Karolinska Institute, respectivamente. [2]

VIP is derivado(a) de a larger precursor molecule, prepro-VIP (170 aminoacidos), codificado(a) por the VIP gene on chromosome 6 in humans. Prepro-VIP is processed into pro-VIP (149 aminoacidos), que is further cleaved and amidated by peptidylglycine alpha-amidating monooxygenase to produce the mature, C-terminally amidated 28-aminoacido peptide. [6]

VIP is widely distributed no(a) central and periferico(a) nervous systems e e produzido(a) por neurons, endocrine cells, and immune cells (B-linfocitos and T-linfocitos). It exerts potente anti-inflamatorio(a), immunomodulatory, and vasodilatory properties. [3]

O(a) sintetico(a) form, Aviptadil (tambem conhecido(a) como RLF-100 or Zyesami), recebeu FDA Composto Orfao Designation para o(a) investigation of ARDS, pulmonar hipertensao, and sarcoidosis, and Fast Track Designation for critico(a) COVID-19 with respiratory failure. The EMA has granted Composto Orfao 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 meia-vida of aproximadamente 1–2 minutes, due to rapido(a) degradacao by dipeptidyl peptidase-4 (DPP-4) e outros(as) serum peptidases. This lability presents significant pharmacological challenges and has driven research into advanced delivery systems incluindo sterically stabilized micelles (SSM), liposomes, and inhalation formulations. [5]

VIP shares 68% homology with PACAP-27 e e relatado(a) to be 100-fold mais potente do que isoproterenol como um(a) bronchodilator and 50-fold mais potente do que prostacyclin at relaxing pulmonar arteries. [7]

1. Alvo Receptor Primarios — VPAC1, VPAC2, and PAC1

VIP exerts its biological effects primariamente by binding to two specific G-protein-coupled receptors (GPCRs) pertencente a the Class B (secretin-like) family: [3]

• VPAC1 (VIPR1): Constitutively expresso(a) em the lung (alveolar type II cells), T-linfocitos, liver, and brain cortex.
• VPAC2 (VIPR2): Predominantly expresso(a) em musculo liso, the suprachiasmatic nucleus (SCN), pancreatic β-cells, and inducible in immune cells upon estimulacao.
• PAC1: VIP also liga-se a 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 como um(a) “Sushi” domain) captures VIP’s central/C-terminal regions (residues 6–28), then the N-terminus of VIP (His1) ativa transmembrane domain 1 (TM1). [9]

2. Canonical Signaling — Gs/cAMP/PKA/CREB Pathway

In a maioria cell types, VIP binding desencadeia the exchange of GDP for GTP no(a) Gαs subunit, activating adenylyl cyclase (AC) and increasing intracellular cyclic AMP (cAMP). Elevated cAMP ativa Protein Kinase A (PKA), que phosphorylates cAMP response element-binding protein (CREB). This pathway drives surfactant production in lungs and insulin secretion no(a) pancreas. [10]

3. Alternative Signaling Pathways

• NF-κB Inhibition (PKA-Independent): In macrofagos and monocitos, VIP inibe nuclear translocation of NF-κB atraves de um(a) PKA-independent mechanism que previne fosforilacao of IκB and inibe IκB kinase (IKK), suppressing pro-inflamatorio(a) cytokine production. [11]
• Dual Gs/AC + Gq/PLC Pathway (Neurons): In GnRH neurons, VIP excitation requer ambos(as) Gs/AC/PKA and Gq/Phospholipase C (PLC) ativacao, levando a PIP2 depletion and inibicao of KCa3.1 channels. [12]
• Epac Pathway (β-Cells): In pancreatic β-cells, VIP signaling envolve ambos(as) PKA (closing ATP-dependent K⁺ channels, causing depolarization and Ca²⁺ influx) e o(a) Epac pathway (mobilizing intracellular Ca²⁺ stores to drive secrecao de insulina). [13]
• EGFR/HER2 Transativacao (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

Immunomodulacao: VIP inibe production of pro-inflamatorio(a) cytokines (TNF-α, IL-6, IL-12) and chemokines in macrofagos and microglia. It shifts T-cell diferenciacao from Th1 toward Th2 and Treg phenotypes, and downregula TLR2 and TLR4 expression on macrofagos and dendritic cells. [11]

Pulmonary System: VIP upregula choline phosphate cytidylyltransferase and C-Fos protein in alveolar type II (ATII) cells, increasing surfactant production. It acts as um(a) potente bronchodilator — 100-fold mais potente do que isoproterenol. [15]

Central Nervous System: In the suprachiasmatic nucleus (SCN), VIP synchronizes neuronal firing via VPAC2, producing long-lasting aumenta in electrical activity (2–4 hours) dependente de the clock gene Per1 and Kv3 channels. [16]

Metabolic System: VIP estimula secrecao de insulina in a dependente de glicose manner via VPAC2 receptors on pancreatic β-cells — negligible at baixo(a) glucose (protecting against hipoglicemia) but potente during hiperglicemia. [13]

5. Pharmacokinetics — Ultra-Short Half-Life

VIP has a serum meia-vida of aproximadamente 1–2 minutes, with rapido(a) degradacao by DPP-4 e outros(as) peptidases no(a) liver, kidneys, and lung. [5] Following IV administration, aproximadamente 45% of a dose distributes para o(a) lungs within 30 minutes. Apparent volume of distribuicao is ~14 mL/kg with a metabolic depuracao rate of ~9 mL/kg/min. [17]

6. Dose-Response Relationships

• CNS Firing Rate (SCN): 1 µM and 10 µM VIP produziu significant aumenta 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 neuroprotecao 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]

🫁 ARDS & COVID-19 (Aviptadil)

Aviptadil tem sido investigado(a) for critico(a) respiratory failure porque it protege alveolar type II cells and bloqueia cytokine storm. In the Phase 2b/3 trial (NCT04311697, n=196), IV aviptadil showed observado(a) effects on inflammatory markers in preclinical respiratory models, 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 como um(a) neuroprotetor(a) 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) aumentou surviving dopaminergic neurons by 43% and reduziu reactive microglia by 57–61%. In Alzheimer’s models, VIP protege against β-amyloid toxicity via ADNP induction. [19] [21]

Veja tambem: BPC-157 para pesquisas relacionadas sobre neuroprotetor(a) research.

🔬 Inflammatory Bowel Disease (IBD)

VIP mantem intestinal barrier homeostasis. VIP-loaded sterically stabilized micelles (VIP-SSM) reversed severe colitis in DSS modelo de camundongos 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 overexpresso(a) em 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 detectado(a) grade IV prostate neoplasia undetectable by standard ¹⁸F-FDG PET or CT. [23] [24]

❤️ Pulmonary Hypertension

Inhaled VIP (100–200 µg) caused potente pulmonar vasodilatacao in 20 sujeitos de estudo — diminuiu pulmonar artery pressure and vascular resistance, melhorou mixed venous oxygen saturation, and aumentou cardiac output — sem significant sistemico(a) observacoes relatadas in populacoes de estudo. VIP is 50-fold mais potente do que prostacyclin at relaxing pulmonar arteries. [7]

🫁 Sarcoidosis

Em um estudo de Fase II trial (n=20), nebulized VIP (50 µg, 4x diariamente por 4 weeks) exerted immunoregulatory effects in sujeitos de estudo with ativo(a) sarcoidosis — significantly reducing TNF-α production in bronchoalveolar lavage (BAL) fluid and increasing regulatory T-cell counts. No sistemico(a) immunosupressao or obvious observacoes relatadas in populacoes de estudo. [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 necessario(a) para synchronization of SCN neurons, influencing sleep and hormonal cycles. [16]

🦠 Sepsis

Em um estudo de Fase I trial (n=8), IV aviptadil (50–100 pmol/kg/hr for 12 hours) alcancou 75% survival (6/8) in sepse-induziu ARDS. VIP inibe alto(a) levels of citocinas inflamatorias e e viewed as um(a) potenteial adjunctive protocolo experimental to antibiotics for septic shock management. [26]

Estudos em Animais

• 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 preveniu dopaminergic neuronal loss and microglial ativacao; bloqueou iNOS, IL-1β, TNF-α expression. [21]
• IBD/Colitis (Mice, Jayawardena 2017): VIP-SSM dose unica reversed severe DSS colitis (P<0.0001 vs DSS); restaurou occludin and DRA expression. Free VIP required alternate-day dosing. [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 estimulou dependente de glicose secrecao de insulina sem hipoglicemia. [13]
• Cardiovascular tolerability (Dogs, Mosley 2019): LBT-3627 at 0.14–1.4 mg/kg SC — transient hemodynamic effects apenas at doses >experimental threshold; resolved within 4 hours. [19]
• SCN Circadian (Mice, Kudo 2013): 1 µM VIP aumentou SCN neuronal firing rate (P<0.05), persisting 4–6 hours post-washout. Requires PER1 and Kv3 channels. [16]

Ensaios Clinicos em Humanos

• COVID-19 ARDS Phase 2b/3 (NCT04311697, n=196): IV aviptadil 50/100/150 pmol/kg/hr × 3 days. Failed desfecho primario; 2× survival at 60 days (OR 2.0, p=0.035), 10× survival in ventilated sujeitos de estudo. IL-6 reduziu significativamente. [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, aumentou Tregs in BAL fluid. No sistemico(a) immunosupressao. [25]
• Pulmonary Hypertension (n=20): Inhaled VIP 100–200 µg. Decreased PA pressure, aumentou cardiac output. Temporary effect. [7]
• Septic ARDS Phase I (n=8): IV aviptadil 50–100 pmol/kg/hr × 12 hours. 6/8 survived; tolerability estabeleceu. [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]

Status Regulatorio

FDA: Composto Orfao Designation (ARDS, pulmonar hipertensao, sarcoidosis); Fast Track Designation (critical COVID-19).

EMA: Composto Orfao Designation (ARDS, sarcoidosis).

CDSCO (India): registered for emergency use in COVID-19 ARDS (2022).

Perfil de tolerabilidade relatado: Most common AEs: hipotensao (26%), diarrhea (33% — reproduz “pancreatic cholera” syndrome), facial flushing, tachycardia. No compound-related serious AEs or mortality in controlled trials. Contraindicated in refractory hipotensao, severe diarrhea, end-stage doenca hepatico(a)a, and pregnancy. [4]