VIP

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]

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]

🫁 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]

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<0.0001 vs DSS); restored 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 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<0.05), persisting 4–6 hours post-washout. Requires PER1 and Kv3 channels. [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]