VIP (Vasoactive Intestinal Peptide): What the Research Literature Covers

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

Vasoactive intestinal peptide (VIP) is a 28-residue neuropeptide of the secretin and glucagon family, first isolated from porcine intestine in 1970, that signals through two class B G protein-coupled receptors, VPAC1 and VPAC2. This article covers the peptide's chemistry and discovery, its receptor pharmacology, the long clinical development history of the synthetic form known as aviptadil, its regulatory status, and the stability problems that make VIP a demanding research reagent.

Discovery and chemistry of a 28-residue peptide

VIP was reported by Said and Mutt in a 1970 Science paper describing a polypeptide isolated from hog small intestine with 28 amino acid residues, chemically distinct from the kinins, substance P, glucagon and secretin. Mutt and Said published the full porcine sequence in 1974 in the European Journal of Biochemistry, using kallikrein cleavage in the determination, and the same year Bodanszky and colleagues reported a total chemical synthesis in the Journal of the American Chemical Society, confirming that the sequence they had assigned was correct. The human peptide, HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH₂, is identical to the porcine one; it carries a C-terminal amide and a free N-terminal histidine, with a molecular weight near 3,326 Da.

Two features of the sequence matter for handling. The histidine-serine N-terminus is the recognition site for dipeptidyl peptidase IV, and the single methionine at position 17 is an oxidation site, so the molecule degrades by two independent routes in biological fluids and by oxidation alone in poorly stored solutions. The sequence is also strongly cationic, with three lysines and three arginines, which drives adsorption to glass and uncoated plastic at low concentrations. The adsorption guide and the oxidation and aliquoting guide cover the practical consequences.

Receptors: VPAC1, VPAC2 and the PAC1 distinction

VIP acts at two receptors that bind it with high affinity, VPAC1 and VPAC2, and only weakly at a third, PAC1, which prefers the related peptide PACAP. The nomenclature was fixed by the IUPHAR subcommittee in a 1998 Pharmacological Reviews report by Harmar and colleagues and updated in the 2012 IUPHAR review in the British Journal of Pharmacology. The IUPHAR/BPS Guide to Pharmacology entry for the family states that VPAC1 and VPAC2 display comparable affinity for VIP, PACAP-27 and PACAP-38, whereas PACAP-27 and PACAP-38 are more than 100-fold more potent than VIP at most PAC1 isoforms. The endogenous ligand set for the family also includes the peptide histidine isoleucineamide (PHI), peptide histidine methioninamide (PHM) and peptide histidine valine (PHV).

All three are class B GPCRs with the large extracellular N-terminal domain characteristic of that class, coupling primarily through Gs to adenylyl cyclase. Couvineau and Laburthe's 2012 review summarizes the two-site binding model in which the peptide's C-terminal half docks in the receptor N-domain and the N-terminal residues then engage the transmembrane core, which is why N-terminally truncated VIP binds but does not activate. A 2022 review by Langer and colleagues in Biomedicines discusses the cryo-EM structures of agonist-bound VPAC1 and PAC1 and the interhelical switches that accompany activation. These structural studies were performed with purified recombinant receptors and synthetic peptides; they describe the mechanism of receptor activation in vitro, not any outcome in an organism.

Aviptadil: programs and status, without outcomes

Aviptadil is the nonproprietary name for synthetic VIP of the native sequence, and it has one of the longer clinical development histories of any neuropeptide. The programs are summarized below as a matter of record; this article does not describe their results. A 2001 profile in Current Opinion in Investigational Drugs by Keijzers documents the first program, run by Senetek, which combined aviptadil with phentolamine and pursued marketing authorizations in several countries in the late 1990s, with an approval recorded in New Zealand by April 2000. Combination products under the name Invicorp were subsequently marketed in some European countries; PubChem lists Invicorp among aviptadil's trade-name synonyms.

The second wave began in 2020, when NRx Pharmaceuticals and a Swiss licensing partner developed aviptadil under the code RLF-100 and the proposed trade name Zyesami for COVID-19-associated respiratory failure. ClinicalTrials.gov records the principal studies: NCT04311697, a phase 2/3 study that began in May 2020 and is listed as completed; NCT04360096 and NCT04536350, inhaled-formulation studies listed as terminated; NCT04844580, an inhaled-formulation phase 2 study listed as completed; NCT05137795, listed as withdrawn; and the NIH-sponsored ACTIV-3b/TESICO platform study (NCT04843761, with the aviptadil arm also registered as NCT06729606), a phase 3 study that began in April 2021 and is listed as completed. The TESICO report, a randomized placebo-controlled comparison of aviptadil and remdesivir published in The Lancet Respiratory Medicine in 2023, is the peer-reviewed record of the largest of those programs. Esendagli and colleagues reviewed the inhaled-formulation rationale in Medical Principles and Practice in 2025.

The status that matters for a research buyer is simple: aviptadil is not an approved drug in the United States. It has not received an FDA approval or an emergency use authorization, and Zyesami is listed on drug-information databases as "not FDA approved." Where aviptadil-containing products have been authorized abroad, they are specific combination formulations from specific license holders. A lyophilized research vial of VIP is not any of those products. The FDA status reference table lists it alongside other research peptides with clinical histories.

Why VIP is hard to keep stable

VIP is among the less stable peptides a laboratory handles, for three reasons that follow from its sequence. First, it is a substrate for dipeptidyl peptidase IV, the serine protease that removes N-terminal dipeptides from peptides with proline or alanine at position two; De Meester and colleagues' 2000 review of the enzyme's natural substrates lists VIP among the neuropeptides it processes, and Mentlein and colleagues showed in 1993 that the same enzyme hydrolyzes the related family members GIP, GLP-1 and PHM in human serum. Any assay that includes serum or cell-conditioned medium therefore sees a shrinking pool of intact VIP over time. Second, the methionine at position 17 oxidizes readily, producing a plus-16 Da species that is still detectable by immunoassay but is not the same molecule. Third, the cationic sequence adsorbs to surfaces, so nominal concentrations in dilute stock solutions can be substantially lower than calculated unless low-binding labware or a carrier protein is used.

These properties shaped the development programs above: the inhaled and stabilized-analog formulations exist because the native peptide has a short lifetime in biological fluids. They also shape the certificate. A lyophilized VIP lot should show an observed mass near 3,326 with no significant plus-16 peak, an HPLC main peak resolved from oxidized and truncated species, and a net peptide content so that the counter-ion fraction is known; stored as a dry powder at freezer temperature and protected from light, the peptide is far more stable than it is in solution. US Prime's VIP 5 mg listing posts a lot-matched certificate with those lines before purchase. For a general overview of storage drivers, see the storage and stability guide.

What the literature establishes and what it does not

The receptor pharmacology of VIP is mature and well replicated: the sequence, the family relationship to PACAP and secretin, the identity of VPAC1 and VPAC2 as its high-affinity receptors, their Gs coupling and their structures are settled science built on purified protein and cell-expression systems over five decades. The peptide's distribution and roles in the gut, lung, immune and nervous systems are documented in rodent and human tissue studies, of which the 2012 IUPHAR review is the standard summary. What the literature does not provide is a research-grade reason to connect a lyophilized vial to any of the clinical programs described above; those programs used specific formulations under controlled protocols, and their results, whatever they were, say nothing about an in vitro reagent. For laboratory purposes VIP is a reference agonist for VPAC receptor assays, a substrate for peptidase studies, and a case study in peptide instability.

Frequently Asked Questions

How many amino acids are in vasoactive intestinal peptide?

Twenty-eight. VIP is a 28-residue peptide with a C-terminal amide, first isolated from porcine intestine by Said and Mutt in 1970 and sequenced by Mutt and Said in 1974. The human and porcine sequences are identical, and the molecular weight is about 3,326 Da.

What receptors does VIP bind?

VIP binds two class B G protein-coupled receptors, VPAC1 and VPAC2, with high and roughly equal affinity, and binds the PAC1 receptor only weakly. All three couple mainly through Gs to adenylyl cyclase. The nomenclature was set by IUPHAR in 1998 and is maintained in the IUPHAR/BPS Guide to Pharmacology.

Is aviptadil the same as VIP, and is it approved?

Aviptadil is the nonproprietary name for synthetic VIP with the native 28-residue sequence. It is not an approved drug in the United States; the 2020-2023 COVID-19 programs did not result in an FDA approval or emergency authorization. Earlier combination products with phentolamine were authorized in some countries outside the US under names such as Invicorp. A research vial of VIP is not any of those products.

Why does VIP degrade so quickly in solution?

Three reasons: it is cleaved at its N-terminus by dipeptidyl peptidase IV in serum and cell-conditioned media, its methionine at position 17 oxidizes, and its strongly cationic sequence adsorbs to glass and plastic. As a lyophilized powder stored cold and dark it is much more stable, which is why research VIP ships as a dry cake.

Citations

1. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217-1218. PMID 5450698
2. Mutt V, Said SI. Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination. Eur J Biochem. 1974;42(2):581-589. PMID 4829446
3. Bodanszky M, Klausner YS, Lin CY, Mutt V, Said SI. Synthesis of the vasoactive intestinal peptide (VIP). J Am Chem Soc. 1974;96(15):4973-4978. PMID 4854585
4. Harmar AJ, Arimura A, Gozes I, et al. International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev. 1998;50(2):265-270. PMID 9647867
5. Harmar AJ, Fahrenkrug J, Gozes I, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol. 2012;166(1):4-17. PMID 22289055
6. Couvineau A, Laburthe M. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol. 2012;166(1):42-50. PMID 21951273
7. Langer I, Jeandriens J, Couvineau A, Sanmukh S, Latek D. Signal Transduction by VIP and PACAP Receptors. Biomedicines. 2022;10(2). PMID 35203615
8. Keijzers GB. Aviptadil (Senatek). Curr Opin Investig Drugs. 2001;2(4):545-549. PMID 11566015
9. 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. Lancet Respir Med. 2023;11(9):791-803. PMID 37348524
10. Esendagli D, Sarı N, Akhan S, et al. Inhaled Aviptadil Is a New Hope for Recovery of Lung Damage due to COVID-19. Med Princ Pract. 2025;34(2):191-200. PMID 39870064
11. De Meester I, Durinx C, Bal G, et al. Natural substrates of dipeptidyl peptidase IV. Adv Exp Med Biol. 2000;477:67-87. PMID 10849732
12. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214(3):829-835. PMID 8100523
13. Fahrenkrug J, Goetzl EJ, Gozes I, et al. VIP and PACAP receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE. 2019. journals.ed.ac.uk
14. ClinicalTrials.gov. Studies of aviptadil (NCT04311697, NCT04360096, NCT04536350, NCT04844580, NCT05137795, NCT04843761, NCT06729606). clinicaltrials.gov
15. PubChem. Aviptadil, CID 16132300. pubchem.ncbi.nlm.nih.gov

This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.

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