VIP: Vasoactive Intestinal Peptide, natural nerve-and-immune messenger
A natural signaling peptide made throughout the body, in the gut, lungs, brain, and immune system, that relaxes smooth muscle, calms inflammation, and helps maintain nerve cells; used as a lab research tool.
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 neuropeptide found throughout the body — in the gut, lungs, brain, and immune system. It is an endogenous signaling molecule, not a synthetic drug: the body produces it continuously, and it plays broad regulatory roles in smooth-muscle tone, immune balance, and nerve-cell maintenance. The peptide was first isolated from porcine intestinal extracts in the early 1970s by Sami Said and Viktor Mutt at the Karolinska Institute, initially characterized as a potent vasodilator. The stored sequence (HSDAVFTDNYTRLRKQMAVKKYLNSILN) represents the linear backbone; the biologically active form carries a C-terminal amide (–NH₂) not shown in the raw sequence, which protects the peptide from carboxypeptidase degradation and is required for full receptor binding.
Despite an attractive pharmacological profile, VIP has never reached routine clinical use as an approved drug. Its very short plasma half-life (under one minute in circulation, per Iwasaki and colleagues, F1000Research 2019), broad receptor distribution, and vasodilatory effects at pharmacologic doses have made therapeutic development difficult. A synthetic form, aviptadil, was investigated extensively for COVID-19-related acute respiratory distress syndrome and pulmonary hypertension; the FDA declined an Emergency Use Authorization for intravenous aviptadil in 2021. VIP is also used in the Shoemaker CIRS (Chronic Inflammatory Response Syndrome) protocol as an off-label intranasal therapy, though that indication lacks large-RCT support and the CIRS diagnostic framework is not accepted by mainstream medicine.
History
VIP was isolated in 1970 from porcine intestinal extracts by Sami Said and Viktor Mutt at the Karolinska Institute, first characterized as a potent vasodilator — which is how it got its name. Over subsequent decades its biology expanded well beyond vascular tone: the peptide was found distributed throughout the central and peripheral nervous systems, immune compartments, and endocrine tissues. By the 1980s it was recognized as a neurotransmitter candidate in nonadrenergic, noncholinergic (NANC) inhibitory innervation, and subsequently its roles in circadian regulation through the suprachiasmatic nucleus and in neuroprotection through the activity-dependent neuroprotective protein (ADNP) pathway were characterized in the literature.
The two receptor subtypes — VPAC1 and VPAC2 — were cloned and characterized as class B GPCRs, and their molecular pharmacology including accessory protein interactions was reviewed by Couvineau and colleagues (British Journal of Pharmacology, 2012). A cryo-EM structure of the human VIP1 receptor in complex with PACAP27 and a Gs heterotrimer was resolved in 2020, providing the first detailed structural picture of ligand engagement (Duan and colleagues, Nature Communications, 2020).
In the 2010s, aviptadil — a pharmaceutical-grade synthetic VIP — was advanced by Relief Therapeutics and NeuroRx for ARDS and pulmonary hypertension, becoming a high-profile investigational therapy during the COVID-19 pandemic. The FDA declined EUA for IV aviptadil in 2021, and the TESICO randomized controlled trial of IV aviptadil plus remdesivir versus placebo did not support clear efficacy in COVID-19 hypoxaemic respiratory failure. Research into VIP for autoimmune diseases including rheumatoid arthritis, lupus, and Graves' disease has continued in parallel.
What it does
VIP acts as a natural anti-inflammatory messenger and smooth-muscle relaxant. In the lungs, it dilates blood vessels and relaxes airway smooth muscle — the property that drove its investigation in pulmonary hypertension and respiratory failure. In the immune system, it shifts the balance away from inflammatory signaling, reducing the output of pro-inflammatory signals and promoting immune-regulatory cell types. In the nervous system, it supports neuron survival and modulates brain-clock timing via the suprachiasmatic nucleus.
The peptide also regulates gut function: it influences ion secretion, smooth-muscle motility, and mucosal immune responses. Iwasaki and colleagues (F1000Research, 2019) reviewed VIP's physiological and pathological roles in the gastrointestinal system, noting effects on circadian rhythms and glycemic control in addition to its classical gut-motility actions.
Evidence
- Human: Moderate. Multiple randomized controlled trials of aviptadil (synthetic VIP) for COVID-19 ARDS produced mixed to negative results — TESICO, a placebo-controlled US trial of IV aviptadil plus remdesivir, did not support clear efficacy in hypoxaemic respiratory failure; a 60-day RCT of IV aviptadil in critically ill COVID-19 patients was also published. A systematic review and meta-analysis of aviptadil therapy in ARDS has been published. Inhaled VIP has been studied in pulmonary hypertension in a published controlled trial showing pulmonary hemodynamic effects. Clinical trials in rheumatoid arthritis demonstrated that VIP modulates Th-cell subset differentiation and cytokine profiles (Martínez and colleagues, International Journal of Molecular Sciences, 2019); separately, VIP gene polymorphisms were shown to predict treatment requirements in early RA (published 2018). A clinical study in Graves' disease found VIP axis dysfunction (published 2020). CIRS use is supported by a single case report and clinical-protocol descriptions, not by a controlled trial.
- Animal: Extensive. Well-studied in rodent models of colitis, arthritis, lupus (Tan and colleagues, Brain Behavior and Immunity, 2015), Sjogren syndrome, Alzheimer's disease, Parkinson's disease, and pulmonary hypertension. VIP decreased β-amyloid accumulation and prevented brain atrophy in the 5xFAD mouse model of Alzheimer's disease (published 2018). A VPAC2-selective synthetic agonist induced regulatory T-cell neuroprotective activity in models of Parkinson's disease (published 2019). VIP ameliorated renal injury in a pristane-induced lupus mouse model by modulating the Th17/Treg balance (published 2019). Colonic delivery of VIP nanomedicine alleviated colitis in preclinical studies and showed promise as an oral capsule format (published 2020).
- In vitro: Moderate. VPAC1 and VPAC2 receptor binding, cAMP elevation, downstream suppression of TNF-α, IL-6, and IL-12, promotion of IL-10, NF-κB inhibition, and regulatory T-cell induction are consistently characterized in cell assays. The 2020 cryo-EM structure of VIP1R bound to PACAP27 (Duan and colleagues, Nature Communications) provides structural grounding for receptor-engagement pharmacology.
Known effects
- Pulmonary vasodilation and bronchodilation — Phase II controlled trial data in pulmonary hypertension (inhaled); mechanistic basis well established
- Anti-inflammatory cytokine modulation — Human clinical trials (RA); extensive animal models
- Regulatory T-cell induction — Preclinical; human clinical signal in RA studies
- Circadian rhythm regulation via SCN — Preclinical/mechanistic
- Neuroprotection (Alzheimer's, Parkinson's models) — Preclinical only
- Gut motility and mucosal immune regulation — Preclinical; mechanistic
- VIP axis dysfunction in Graves' disease — Single clinical study
- Aviptadil for COVID-19 ARDS — Multiple RCTs; did not establish clear efficacy
Safety signals
Acute hemodynamic effects are the primary safety signal: VIP is a potent vasodilator, and clinically meaningful hypotension at pharmacologic doses is well documented across clinical trial exposures. The peptidelist source notes concurrent use with nitrates, phosphodiesterase-5 inhibitors (sildenafil, tadalafil), alpha-blockers, or antihypertensives carries theoretical additive hypotension risk based on pharmacology, though formal human drug-interaction studies are essentially absent.
Reported adverse effects from clinical use include nasal congestion (intranasal formulations), mild diarrhea, and flushing — consistent with VIP's vasodilatory and secretomotor pharmacology. Caution is noted in hypotension, hemodynamic instability, severe aortic stenosis, hypertrophic obstructive cardiomyopathy, and active gastrointestinal bleeding based on the same vasodilatory mechanism. No adequate human safety data exists for use in pregnancy or breastfeeding.
Long-term safety of chronic exogenous VIP administration is not established in controlled trials. Most controlled exposure data comes from acute-window infusion protocols (28–60 days in the ARDS trials). The safety profile of months of daily intranasal use is uncharacterized at the controlled-trial level.
Product quality is a practical concern: aviptadil used in clinical trials was pharmaceutical-grade GMP-manufactured material; research-chemical VIP sold outside licensed channels is not manufactured to those standards, and VIP is chemically fragile with a very short plasma half-life, making formulation integrity a first-order issue.
Regulatory status
- US (FDA): Not approved for any indication. Aviptadil EUA for IV use in COVID-19 ARDS was declined in 2021. Compounded intranasal and injectable VIP has historically been available through 503A compounding pharmacies under individualized prescription; the broader regulatory environment for peptide compounding is tightening.
- EU (EMA), UK (MHRA), Australia (TGA): Not approved for any indication per available sources.
- WADA: Not explicitly listed on the Prohibited List per available sources; however, the S0 category (unapproved substances) applies to any substance without regulatory approval for human therapeutic use — which describes VIP. Athletes subject to WADA-governed testing should confirm status with their anti-doping authority.
Mechanism
VIP binds to VPAC1 and VPAC2 — class B G-protein-coupled receptors coupled to adenylyl cyclase (Gαs). Receptor activation elevates intracellular cAMP, which drives downstream suppression of pro-inflammatory cytokine production (TNF-α, IL-6, IL-12) and upregulation of anti-inflammatory IL-10. VIP inhibits NF-κB activation and reduces oxidative stress in immune and epithelial cells. In the adaptive immune compartment, VIP promotes differentiation of regulatory T cells (Tregs), contributing to immune tolerance — reviewed comprehensively by Martínez and colleagues (IJMS, 2019) and Gomariz and colleagues (Frontiers in Endocrinology, 2019).
In the lung, the Gαs/cAMP pathway mediates smooth-muscle relaxation in pulmonary vascular and airway smooth muscle. In the nervous system, VIP functions as a neurotrophic factor, modulates synaptic plasticity, and drives neuroprotective signaling partly through induction of ADNP (activity-dependent neuroprotective protein). VIP also entrains circadian rhythms through VIP-ergic projections from the suprachiasmatic nucleus to downstream tissues.
The cryo-EM structure of human VIP1R in complex with PACAP27 and a Gs heterotrimer (Duan and colleagues, Nature Communications, 2020) revealed the structural basis for class B GPCR activation at this receptor. The molecular pharmacology of VPAC1 and VPAC2 — including receptor structure and interaction with accessory proteins — is reviewed by Couvineau and colleagues (British Journal of Pharmacology, 2012).
VIP's plasma half-life is less than one minute under physiological conditions (Iwasaki and colleagues, F1000Research, 2019), driven by rapid proteolytic degradation. This short half-life is the core pharmacokinetic challenge for all therapeutic applications.
Open questions
- CIRS as a controlled indication: No randomized controlled trial has evaluated VIP specifically for CIRS. The CIRS diagnostic framework is not accepted by mainstream medicine; the evidence base for this use is protocol-driven, not trial-driven.
- Intranasal pharmacokinetics: How much VIP reaches systemic circulation and CNS compartments from an intranasal dose, and with what inter-individual variability, has not been characterized in controlled human studies.
- Long-term safety of chronic administration: Most controlled exposure data is from acute infusion protocols. Safety of months of daily intranasal or subcutaneous VIP use is essentially uncharacterized at the RCT level.
- Route-comparative efficacy: Whether intranasal, inhaled, subcutaneous, or IV VIP produce equivalent clinical effects in comparable populations has not been formally studied.
- Responder phenotyping: Predictors of VIP response — receptor expression levels, baseline inflammatory state, comorbidities — have not been mapped in clinical populations.
Related peptides
- PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) — closely related class B GPCR ligand that shares VPAC1 and VPAC2 with VIP while additionally activating the PAC1 receptor; substantial structural homology at the N-terminus and overlapping neuroprotective biology
- Secretin — member of the same secretin/glucagon/VIP peptide superfamily; acts at a distinct class B GPCR but shares evolutionary lineage and some signaling overlap in gut and pancreatic contexts
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could a natural signaling peptide, applied directly as eye drops, cool the inflammation that makes dry eye so painful and hard to treat?
If this holds, people with chronic dry eye could have a new type of anti-inflammatory drop that works by a completely different mechanism than current options. Because the peptide stays in the eye and is not absorbed into the bloodstream, the blood-pressure side effects that block this compound from being used as an injection would not apply.
Could injecting a natural peptide around the eye socket fix the exact signaling problem behind Graves' eye disease, reducing swelling without the risks of whole-body treatment?
Graves' orbitopathy causes painful, disfiguring eye protrusion and has very few treatment options. If the peptide corrects the documented signaling deficit in the tissue responsible, it could slow or stop the disease in a way that is mechanistically matched, not just symptom management, and for the many patients who cannot tolerate steroids or cannot access expensive newer drugs.
If you swap out the parts of a promising peptide that enzymes destroy within seconds, could you get a version that survives long enough to actually work as a medicine?
Right now, VIP breaks down in the bloodstream in under a minute, which makes it nearly impossible to dose as a drug. If targeted substitutions extend that to 30 minutes or more, it could unlock affordable injectable or nasal-spray treatments for conditions like rheumatoid arthritis, inflammatory bowel disease, and nerve damage, without needing the complex slow-release packaging that adds cost and development risk.
What if the anti-inflammatory action of a peptide being tested for lung disease runs through a different molecular switch than the one researchers have been designing around?
Clinical trials of aviptadil for severe lung failure have produced inconsistent results, which could partly be explained by this mismatch. If the lung actually relies on a different receptor subtype, drug developers could redesign analogs to target that subtype more precisely, potentially rescuing a whole class of treatments for respiratory disease that have so far underperformed.
Does VIP turn down inflammation through one well-known molecular chain reaction, or through a separate route that would require a completely different drug strategy?
The answer determines how you build better VIP-based drugs. If the main route runs through one pathway, you can engineer analogs that maximize that signal and predict they will work. If a parallel pathway dominates, the obvious engineering approach could fail entirely, and you would need to redesign from scratch. Getting this right matters for anyone with rheumatoid arthritis, Crohn's disease, or other conditions where VIP analogs are being developed.
If a peptide is mostly disordered in solution but still binds its target with very high affinity, which part of it locks into shape first, and does breaking that part destroy the binding?
If a specific short cluster of amino acids acts as the folding trigger that lets the rest of the peptide seat correctly into its receptor, designers can protect that anchor while freely modifying the enzyme-vulnerable sites nearby. This could point directly to where stabilizing chemical modifications should and should not be placed, speeding up the development of VIP analogs that survive long enough to work as drugs.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 0.11 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{pep10468,
sequence = {HSDAVFTDNYTRLRKQMAVKKYLNSILN},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}