VIP Research, Specifications & Scientific Information

Introduction

VIP — vasoactive intestinal peptide — is a 28-residue endogenous peptide that has been known and characterised for more than fifty years. Its receptors are identified, its signalling is understood, and its physiological roles in the gut, the vasculature and the immune system are documented at review level ^{[3, 4]}.

It is also the subject of one of the clearest recent illustrations of how a well-founded preclinical rationale can fail in a trial. During the COVID-19 pandemic the synthetic peptide, under the International Nonproprietary Name aviptadil, entered critical-care trials on the strength of non-clinical findings in pulmonary cells: surfactant upregulation, cytokine inhibition, protection against cytopathy ^[2]. A 196-participant trial missed its primary endpoint while reporting a favourable secondary survival analysis ^[2]. A subsequent federally funded trial, TESICO, analysed 461 participants and found no significant improvement in clinical outcomes to day 90 ^[1].

This page reports the receptor pharmacology, which is solid, and the clinical record, which is negative on its primary endpoints, without letting either substitute for the other.

What Is VIP?

VIP is an endogenous peptide of 28 residues, 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, carrying a C-terminal amide that is required for receptor activation.

It belongs to the secretin/glucagon superfamily — the same structural family as PACAP, secretin, glucagon, GIP and GLP-1 — and acts at class B1 G protein-coupled receptors. It functions as a neurotransmitter in the enteric and autonomic nervous systems, as a vasodilator, and as an immunomodulator, and it is distributed widely enough that no single organ system owns it ^{[3, 4]}.

The synthetic peptide identical to the human sequence is named aviptadil. PubChem carries it under compound identifier 16132300, with the FDA/NCATS UNII code A67JUW790C and an acetate salt form under UNII K24S5TZM78.

It has not been approved by the U.S. Food and Drug Administration for any indication. A combination product containing VIP with phentolamine has been licensed for a urological indication in some other jurisdictions, under those jurisdictions' own licences, and that is the extent of the compound's regulatory standing anywhere.

VIP Specifications

The synthetic peptide identical to human vasoactive intestinal peptide holds the International Nonproprietary Name aviptadil, and the identifiers on this page are carried against that name: PubChem compound identifier 16132300, FDA/NCATS UNII code A67JUW790C, and an acetate salt form under UNII K24S5TZM78. The molecule is a 28-residue linear peptide with a free N-terminus and a C-terminal amide; the amide is required for receptor activation, and its hydrolysis to the free acid costs one dalton in a 3.3 kDa peptide, which routine intact-mass measurement will not resolve. VIP belongs to the secretin/glucagon superfamily and is closely related in sequence to PACAP, with which it shares two of its three receptors — a point of real pharmacological consequence, since a VIP preparation cannot be assumed to act only at VIP-preferring receptors. The single methionine at position 17 is an oxidation liability adding sixteen daltons when it forms the sulphoxide.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does VIP Work?

Through two receptors, VPAC1 and VPAC2, both class B1 G protein-coupled receptors signalling principally through Gs and cyclic AMP ^[3].

Two features of that arrangement shape how the compound's effects should be read.

The receptors are not VIP-exclusive. PACAP, a closely related peptide from the same superfamily, is also an agonist at VPAC1 and VPAC2 and has a third receptor, PAC1, of its own. An effect observed after administering VIP cannot be assigned to a VIP-specific pathway without evidence beyond the observation itself.

The receptors are widely distributed. VPAC receptors are present in gut, lung, vasculature and immune cells. A systemically administered agonist therefore engages several systems at once, and the resulting profile — vasodilatation, altered gut motility, immunomodulation — is the expected consequence of that distribution rather than an unexpected complication.

The specific rationale for the respiratory trials sat on top of this general pharmacology. The preclinical case, as the 2022 trial report summarises it, was that VIP upregulates surfactant production, inhibits cytokine synthesis, prevents cytopathy, and blocks viral replication in pulmonary cells ^[2]. That is a coherent and specific hypothesis about a defined disease process. It is also exactly the kind of hypothesis a randomised trial exists to test, and the test result is in the human section below.

VIP Mechanism of Action

In vitro research

Receptor identity and signalling. VPAC1 and VPAC2 are established as the peptide's receptors, and their signalling through Gs and cyclic AMP, their tissue distribution and their role in gastrointestinal physiology are set out in current reviews of the field ^[3].

Immunomodulatory activity. The VIP axis has documented activity in inflammatory and autoimmune processes, reviewed with a view to clinical application ^[4]. That review describes a research programme rather than established treatments.

What receptor characterisation does not settle. Identifying a receptor and its signalling pathway establishes that a molecule has a defined molecular action. It does not establish that engaging that receptor in a diseased human produces benefit, which is a separate question answered only by trials.

Findings in this section were obtained in receptor and cellular systems. Nothing in them establishes anything about intact animals or about humans.

What Is VIP Being Researched For?

• Acute hypoxaemic respiratory failure — the largest clinical programme, conducted during the COVID-19 pandemic and concluded with a negative phase 3 trial ^{[1, 2]}.
• Inflammatory and autoimmune disease — at the level of the VIP axis as a target rather than of a specific candidate compound ^[4].
• Gastrointestinal physiology and pathophysiology — the peptide's original and best-established domain ^[3].
• Pulmonary vascular tone — including work with stabilised analogues in rodent lung preparations ^[5].

Each of those is research on an investigational product or on an endogenous signalling system. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Human Research on VIP

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

TESICO — COVID-19-associated acute hypoxaemic respiratory failure, 2023

Population. 473 participants enrolled between April 2021 and May 2022 at 28 sites in the United States; 471 randomly assigned in the aviptadil comparison, with 461 in the modified intention-to-treat population — 231 receiving aviptadil and 230 matched placebo. Median age 57 years, 39% female, 53% Black, Hispanic, Asian or other. 94% were in intensive care at baseline; 59% were receiving high-flow nasal oxygen or non-invasive ventilation, 40% invasive mechanical ventilation, and 1% extracorporeal membrane oxygenation ^[1].

Endpoint and design. A randomised, placebo-controlled trial with a 2 × 2 factorial component against remdesivir, stratified by disease severity. Aviptadil was administered as a daily 12-hour intravenous infusion for three days with escalating targets. The primary efficacy endpoint was an ordinal clinical outcome assessed at day 90 ^[1].

Result. The odds ratio for being in a better category of the primary endpoint at day 90, from a model stratified by baseline severity, was 1.11 (95% CI 0.80–1.55; p = 0.54). The authors' interpretation is that aviptadil did not significantly improve clinical outcomes up to day 90 compared with placebo ^[1].

Weight. This is the most informative trial on this compound: adequately sized, prospectively designed, publicly funded rather than sponsor-funded, and conducted in the indication where the hypothesis had been most strongly advanced. Its confidence interval is narrow enough to exclude a large benefit.

The earlier randomised trial, 2022

Population and design. 196 participants with COVID-19 respiratory failure at ten United States hospitals, randomised 2:1 to three days of intravenous aviptadil or placebo. The primary endpoint was being alive and free from respiratory failure at day 60 ^[2].

Result as reported. The primary endpoint did not reach statistical significance — odds ratio 1.6, 95% CI 0.86–3.11, when controlling for baseline ventilation status as prespecified. Secondary analyses reported a two-fold odds of survival at 60 days (OR 2.0, 95% CI 1.1–3.9, p = 0.035), improvement in the respiratory distress ratio, and reduced interleukin-6 release by day 3 (p = 0.02). Subgroup analyses identified significance among participants receiving high-flow nasal oxygen at baseline and among those on mechanical ventilation. The authors' own stated conclusion records both halves: that the primary endpoint did not reach significance, indicating no difference between aviptadil and placebo, and that they regard the benefit-risk balance as favourable ^[2].

Limitations. 196 participants, 2:1 allocation, and a conclusion that rests on secondary and subgroup analyses after a missed primary endpoint. That pattern is the classic setting for a result that does not replicate, and in this case it did not: the larger trial that followed tested the same hypothesis and was negative ^[1].

How to read the two together

They do not conflict on the question each was designed to answer — neither met its primary endpoint. They differ in what their authors emphasised. Where a small trial's secondary analysis and a large trial's primary analysis point in different directions, the large trial's primary analysis is the better evidence, and a compound with two randomised trials and no met primary endpoint has not been shown to work in that indication.

Preclinical Research on VIP

Animal research

Stabilised analogue in rodent lung. RO 25-1553, a stable VIP analogue, was characterised for vasodilatory effect in murine and rat lungs ^[5]. The study is a useful marker of where this field's pharmacology sits: the native peptide's short half-life is enough of an obstacle that much of the preclinical vascular work uses engineered analogues rather than VIP itself.

What that implies for the native peptide. Results obtained with a stabilised analogue are results about that analogue. They support the general proposition that VPAC receptor agonism produces vasodilatation in the pulmonary circulation; they do not transfer quantitatively to the native peptide, whose exposure profile is entirely different.

Findings described in this section were observed in mice and rats. Nothing in them establishes anything about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

VIP vs Related Compounds

Against PACAP

PACAP is the closest relative, sharing VPAC1 and VPAC2 and adding PAC1 of its own. Overlapping receptor pharmacology means neither peptide's effects can be assumed to be specific to it, and studies that attribute an outcome to one without excluding the other are incomplete on that point.

Against the rest of the secretin superfamily

Secretin, glucagon, GIP and GLP-1 share the class B1 receptor architecture and the same general signalling logic. Their receptors are distinct, and the family resemblance is structural rather than functional.

Against stabilised analogues

RO 25-1553 and similar engineered peptides exist because the native molecule is cleared within minutes ^[5]. A page about VIP should not import their results, and a preparation of native VIP does not behave like them.

Against oxytocin

Oxytocin is the other endogenous peptide in this library with approved products in one physiological role and a large investigational literature that has not matched them. The parallel is methodological — a well-characterised molecule with a defined receptor proving difficult to convert into a treatment outside its native function — and not pharmacological.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

VIP is a linear 28-residue peptide of molecular formula C147H237N43O43S and average mass 3326.8 g/mol, under PubChem compound identifier 16132300.

The C-terminal amide is required and is hard to verify. Amidation is necessary for receptor activation, and hydrolysis to the free acid costs one dalton. On a 3.3 kDa peptide that difference sits inside the isotope envelope of a routine intact-mass measurement, so confirming the amide requires a method chosen for the purpose.

One methionine, and it oxidises. Methionine at position 17 forms the sulphoxide readily, adding sixteen daltons and producing a species that is chromatographically distinct from the parent but frequently incompletely resolved. This is the most common degradation product of the peptide and the one a certificate of analysis should address.

Highly basic, and adsorptive. Three lysines and two arginines make the peptide strongly cationic at physiological pH. Peptides of this size and charge adsorb appreciably to glass and to some plastics from dilute solution, so nominal and actual concentrations diverge in dilute preparations unless carrier protein or a suitable surface is used.

Length brings the usual synthesis burden. At 28 residues, deletion sequences missing a single residue are the characteristic impurity of solid-phase synthesis. They differ from the target by roughly 3% of its mass and co-elute closely; establishing the sequence requires enzymatic digestion and mapping rather than an intact-mass measurement.

Two tyrosines give a modest chromophore. There is no tryptophan, so absorbance at 280 nm comes from the two tyrosines and is weaker than for a tryptophan-containing peptide of similar size. Both tyrosines are also oxidation sites.

Frequently Asked Questions

Scientific References

1. Brown SM, Barkauskas CE, Grund B, et al.. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial The Lancet. Respiratory medicine; 2023. PMID 37348524 doi:10.1016/S2213-2600(23)00147-9
2. Youssef JG, Lavin P, Schoenfeld DA, et al.. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial Critical care medicine; 2022. PMID 36044317 doi:10.1097/CCM.0000000000005660
3. Iwasaki M, Akiba Y, Kaunitz JD. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system F1000Research; 2019. PMID 31559013 doi:10.12688/f1000research.18039.1
4. Martínez C, Juarranz Y, Gutiérrez-Cañas I, et al.. A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases International journal of molecular sciences; 2019. PMID 31861827 doi:10.3390/ijms21010065
5. Yin J, Wang L, Yin N, et al.. Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs PloS one; 2013. PMID 24069452 doi:10.1371/journal.pone.0075861

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.