VIP nerve-and-gut calming hormone
A natural signaling molecule made throughout the nervous and immune systems that reduces inflammation and coordinates the gut, lungs, and brain; studied as a potential treatment for inflammatory and autoimmune conditions, but not yet an approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Vasoactive intestinal peptide (VIP) is a 28-amino-acid signaling molecule produced throughout the nervous and immune systems. It acts as a neurotransmitter, hormone, and anti-inflammatory messenger simultaneously — one of the few endogenous peptides that bridges the gut, brain, lung, and immune system in a single molecule. VIP has been studied for decades as a potential therapeutic agent in inflammatory and autoimmune conditions. The stored sequence (HSDAVFTDNYTRLRKQAVKYLNSILNGK) is the canonical mammalian backbone, conserved across human, porcine, bovine, and rat; the active peptide carries a C-terminal amide (–NH₂) that is absent from the raw one-letter sequence shown here.
History
VIP was isolated in 1970 by Sami Said and Viktor Mutt from porcine small intestine (Said and Mutt, 1970). The peptide was named for its pronounced vasodilatory effect observed on initial characterisation. Said and Mutt described it as a "vasoactive octacosapeptide related to secretin and to glucagon," placing it within the secretin/glucagon superfamily — a group that includes glucagon, secretin, PACAP, and GIP. Its receptor was cloned decades later; the two primary VIP-binding GPCRs are now designated VPAC1 and VPAC2 (formerly VIP1 and VIP2) by IUPHAR nomenclature, reflecting that both receptors bind VIP and PACAP with equal high affinity (Couvineau and Laburthe, 2012).
What it does
VIP acts at its receptors to broadly dampen inflammation. In immune cells, binding VPAC1 reduces the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12 and suppresses the transcription factor NFκB. In smooth muscle, VIP triggers relaxation via cyclic AMP signalling, which explains its original characterisation as a vasodilator. In the gut, it regulates motility and mucosal secretion. In the central nervous system, it serves as a neurotransmitter with roles in circadian rhythm synchronisation and neuroprotection. Because VPAC1 is constitutively expressed on resting T cells, monocytes, and neutrophils, VIP signalling through this receptor exerts tonic anti-inflammatory control during acute immune responses (Smalley and colleagues, 2009).
Evidence
- Human: VPAC1 receptor expression in peripheral blood mononuclear cells from 125 early arthritis patients was found to correlate inversely with disease activity (DAS28 scores) and IL-6 levels, supporting VPAC1 as a disease-activity biomarker (Seoane and colleagues, 2016). No large-scale therapeutic trials using native VIP have been completed; the short in vivo half-life and systemic vasodilatory effects of the parent peptide have limited its clinical development.
- Animal: In collagen-induced arthritis models, VIP administration reduced incidence and severity of arthritis, prevented joint swelling, and limited cartilage and bone destruction (Gomariz and colleagues, 2019). VIP treatment increased survival in murine lethal-LPS sepsis models. VPAC1-selective agonists outperformed VPAC2-selective agonists for arthritis amelioration in these models.
- In vitro: VIP activates adenylyl cyclase through VPAC1 with sub-nanomolar potency. The ChEMBL bioassay record for this compound (CHEMBL3102927) reports an EC50 of 1.49 nM at human VPAC1. Alanine-scanning studies established that positions His1, Val5, Arg14, Lys15, Lys21, Leu23, and Ile26 are critical for VPAC1 receptor activation, while positions 11, 22, and 28 govern selectivity between VPAC1 and VPAC2 (Nicole and colleagues, 2000).
Known effects
- Anti-inflammatory / immunomodulatory — reduces TNF-α, IL-6, IL-12, and nitric oxide in macrophages and monocytes; promotes Th2 over Th1 balance; expands regulatory T cells; reduces Th17 response (preclinical / ex vivo human data)
- Vasodilation and smooth muscle relaxation — original pharmacological characterisation; primary reason for clinical development challenges
- Gut motility regulation — neuromodulator of intestinal secretion and motility
- Neuroprotection / neurotrophic support — inhibits microglia-induced neurodegeneration; supports corneal epithelial wound healing in preclinical models
- Circadian rhythm regulation — critical neurotransmitter role in suprachiasmatic nucleus pacemaker function
Safety signals
Systemic VIP infusion causes dose-dependent hypotension, facial flushing, and diarrhoea — effects that reflect VIP's potent vasodilatory and secretory actions at VPAC1 and VPAC2 in peripheral tissues. Gomariz and colleagues (2019) note these cardiovascular and gastrointestinal effects as primary barriers to systemic therapeutic use. Research groups have therefore investigated nanoparticle encapsulation and selective-agonist strategies to separate anti-inflammatory effects from the vasodilatory and secretory side effects. No genotoxicity or oncogenic signal has been associated with endogenous VIP in the published literature reviewed.
Regulatory status
- US / EU: Not approved as a drug. Endogenous human peptide. No IND-level clinical programme for native VIP has advanced to Phase II or III registration.
- Research reagent use: Available commercially (CAS 40077-57-4) as a reference standard and pharmacological tool.
- WADA: Not listed on the WADA prohibited list. Endogenous peptide with no established performance-enhancing use at physiological concentrations.
Mechanism
VIP belongs to the glucagon/secretin superfamily (class B GPCRs). Its 28-residue sequence adopts an α-helical conformation from approximately Val5 to Asn24, with more flexible N- and C-terminal regions. This helix-coil architecture underpins the two-domain binding model: the central and C-terminal residues of VIP dock into the large N-terminal ectodomain of VPAC1, while the N-terminal residues (particularly His1) insert into the transmembrane bundle to trigger receptor activation (Couvineau and Laburthe, 2012; Couvineau and colleagues, 2012).
At VPAC1, binding couples preferentially to Gαs, activating adenylyl cyclase and raising intracellular cAMP. PKA downstream of cAMP phosphorylates CREB, blocks its interaction with NFκB co-factors, and suppresses transcription of pro-inflammatory genes. VPAC1 can also interact with RAMP2, which augments inositol phosphate production without altering cAMP output — a parallel Gαq/PLC branch (Couvineau and Laburthe, 2012). After agonist exposure, GRK-mediated phosphorylation of C-terminal and IC2 serine/threonine residues drives β-arrestin recruitment and receptor internalisation; notably, VPAC1 does not recycle to the cell surface within 2 h of agonist washout, in contrast to VPAC2 (Langer, 2012).
High-resolution cryo-EM structures show VIP forming seven hydrogen bonds with VPAC1 — fewer than the ten formed by PACAP27 — yet VIP maintains selectivity for VPAC1 over PAC1R because PAC1R's more constrained extracellular loop 3 topology raises the energy barrier for VIP engagement (Piper and colleagues, 2022).
Open questions
- Native VIP's very short plasma half-life (minutes, due to rapid proteolytic degradation) and systemic vasodilatory effects have blocked clinical translation; stable, VPAC1-selective analogs or nanoparticle delivery strategies remain active research directions
- Whether VPAC1 expression level in peripheral blood cells can serve as a predictive biomarker for anti-inflammatory therapy response in early rheumatoid arthritis has not been prospectively validated
- The structural basis for receptor selectivity between VPAC1 and VPAC2 is now partially resolved by cryo-EM (Piper and colleagues, 2022), but no crystal structure of [Ala11,22,28]VIP in complex with VPAC1 has been solved
- Circadian rhythm and neuroprotective applications of VPAC1 agonism have been characterised largely in rodent models; human CNS pharmacology data are sparse
Related peptides
- VIP / aviptadil — the same endogenous 28-mer in a card covering its pharmaceutical development as aviptadil, clinical research in ARDS and pulmonary hypertension, and off-label investigational use
- (Ala11,22,28)-VIP — synthetic VPAC1-selective analog with triple alanine substitutions at positions 11, 22, and 28 that confer >1,000-fold selectivity for VPAC1 over VPAC2 (Nicole and colleagues, 2000)
- Secretin — the founding member of the secretin/glucagon superfamily; shares the N-terminal His-Ser motif and class B GPCR pharmacology with VIP but acts at the secretin receptor on pancreatic ductal cells
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| EC50 | 1.49 nM | GPCRDB/ChEMBL |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10482,
sequence = {HSDAVFTDNYTRLRKQAVKYLNSILNGK},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}