VIP: Vasoactive Intestinal Peptide in Research

VIP is vasoactive intestinal peptide, a 28-residue neuropeptide with the sequence HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2, isolated from hog small intestine by Sami Said and Viktor Mutt in 1970. It belongs to the glucagon-secretin superfamily and signals through two class B1 G protein-coupled receptors, VPAC1 and VPAC2, both of which couple to Gs and raise cyclic AMP. Aviptadil is the international nonproprietary name for synthetic VIP; no application containing it has been approved by the FDA.

At 3,326.8 g/mol, VIP is one of the larger peptides handled as a research reagent, and its properties follow from that size: an amphipathic helix, a single oxidation-prone methionine, and a C-terminal amide that is required for receptor activity. This profile covers identity, the precursor, receptor pharmacology, research systems, regulatory status and handling.

VIP at a glance

Aviptadil and VIP are the same molecule; the formula, mass and sequence in PubChem are identical for both records. The separate name and CAS number exist because a compound in development receives an international nonproprietary name, which is a naming decision rather than a regulatory status.

The precursor, and the peptide encoded beside it

The human VIP gene produces a 170-residue precursor, prepro-VIP, that carries two bioactive peptides rather than one.

PHM-27, named for its N-terminal histidine, C-terminal methionine and length, is therefore co-encoded with VIP and released from the same precursor. Both C-terminal amides come from the same processing step: a Gly-Lys-Arg motif following each peptide is cleaved and the exposed glycine is converted to the amide. This is the same chemistry described in how peptides are made, where a synthetic route reaches the amide by choosing an amide-forming resin instead.

VIP sits in the glucagon family, whose other members include PACAP, secretin, glucagon, the glucagon-like peptides, gastric inhibitory polypeptide and growth hormone-releasing hormone. The family relationship is why VIP and PACAP share receptors, and why sequence similarity in the N-terminal third of these peptides is so high.

Isolation in 1970

Said and Mutt reported the peptide twice in 1970. A note in Nature in February described a vasodilator peptide from normal gut; the fuller report in Science in September described the isolation from the small intestine of the hog of a polypeptide with, in the authors' words, "potent and diverse biological action", including systemic vasodilation and effects on cardiac output, respiration and blood glucose. The paper stated the chain length as 28 residues and established that the compound was chemically distinct from the kinins, substance P, glucagon and secretin — the peptides it might otherwise have been mistaken for in a gut extract.

The name records the discovery assay rather than the receptor biology: "vasoactive" because vasodilation was the screening readout, and "intestinal" because the hog intestine was the source. Both parts of the name are now historical; the peptide is expressed widely in the central and peripheral nervous systems.

VPAC1, VPAC2 and PAC1

VIP and PACAP act on three receptors, and the nomenclature was settled by a 2012 review from the receptor nomenclature committee, published in the British Journal of Pharmacology.

All three are class B1 (secretin-like) GPCRs, a family that also contains the receptors for parathyroid hormone, corticotropin-releasing factor and calcitonin. The shared architecture is a large extracellular domain that captures the C-terminal half of the peptide, and a transmembrane core that the peptide's N-terminal residues insert into. Ligand binding activates the cyclic AMP pathway through Gs; VPAC2 has also been reported to couple to phospholipase C.

Two 2022 cryo-electron microscopy studies put structures behind that model. Piper and colleagues determined active, Gs-coupled VIP-VPAC1R, PACAP27-VPAC1R and PACAP27-PAC1R complexes and reported fewer stable contacts between VPAC1R and VIP than with PACAP27, along with more dynamic interaction of VIP with extracellular loop 3. Xu and colleagues determined the VPAC2-PACAP27-Gs complex and found the receptor's N-terminal α-helix inserted into a cleft between the peptide and extracellular loop 1; truncating or extending that helix lowered receptor-mediated cyclic AMP accumulation.

For assay design, the consequence is the same one that applies to any shared-ligand family: a readout from a preparation expressing both VPAC1 and VPAC2 cannot be assigned to one subtype. Single-receptor expression in HEK293 or CHO cells, with a cyclic AMP readout and PACAP27 and PACAP38 as comparators, is the standard arrangement.

Research systems

The VIP literature is large and old enough that the assay formats span several generations of method.

• Recombinant receptor assays. Cell lines expressing one human receptor, with cyclic AMP accumulation, a cyclic AMP biosensor or β-arrestin recruitment as the readout. This is where selectivity between VIP and the PACAP forms is measured.
• Structural biology. Cryo-electron microscopy of agonist-bound receptor-G protein complexes, supported by molecular dynamics simulation, as in the two 2022 studies above. VIP is used here as the reference agonist for VPAC1 and VPAC2.
• Tissue and cell preparations. Isolated smooth muscle, pancreatic islet, and immune cell cultures in which the peptide's actions were originally characterized. The UniProt annotation summarizes the reported physiology: vasodilation, lowered arterial blood pressure, myocardial contractility, glycogenolysis and relaxation of smooth muscle in trachea, stomach and gall bladder.
• Peptide chemistry. VIP analogs are a standing test case for stabilizing a class B1 agonist, since the native peptide is cleared quickly and is sensitive to proteolysis at several points along the chain.

Regulatory status

Aviptadil is not an approved drug in the United States. A search of the FDA Drugs@FDA data set returns no approved application with aviptadil as an active ingredient. It has been studied in registered human trials, including Phase 2 and Phase 3 studies in severe COVID-19 listed on ClinicalTrials.gov under the sponsor's product name; those records show statuses of terminated or withdrawn, and a registered or completed trial is not an approval.

Anhydrolabs supplies VIP as a research reagent for in-vitro laboratory use, not for human or veterinary diagnosis, treatment, or consumption. The terms of supply are on the research use page.

Handling VIP in the laboratory

VIP is supplied as a lyophilized powder in vacuum-sealed vials, and in 10-vial kits. At 28 residues it behaves more like a small protein than like a short synthetic peptide, and the sequence dictates most of the precautions.

• Charge and adsorption. The chain carries Arg12, Arg14, Lys15, Lys20 and Lys21 against two aspartates, so it is strongly cationic near neutral pH. Cationic amphipathic peptides adsorb to glass and to untreated plastic; low-binding tubes and a carrier protein in dilute working solutions prevent a large fraction of a nanomolar solution from disappearing onto the walls of the vessel.
• Methionine 17. The single sulfur in the formula is this residue, and it is the most reactive site in the molecule. Oxidation to the sulfoxide adds 16 Da and is visible by mass spectrometry. Minimize headspace air, avoid oxidizing buffers and keep solutions cold and dark.
• The C-terminal amide and the asparagines. Receptor activity depends on the C-terminal asparagine amide. Asn-Gly and Asn-Ser sequences deamidate fastest at alkaline pH, so stocks are normally held near neutral or mildly acidic.
• Solubility. The peptide dissolves in water and in dilute acetic acid. As an amphipathic helix former it can aggregate at high concentration or at a pH near its isoelectric point; preparing a concentrated stock in a slightly acidic solution and diluting into buffer at the bench is the usual approach. See how to reconstitute peptides.
• Concentration checks. With two tyrosines and no tryptophan, absorbance at 280 nm is weaker than for a Trp-containing peptide but still usable, and amino acid analysis is the reference method when a precise concentration matters.
• Storage and lifetime. Sealed vials are held cold, dry and dark, with −20 °C the usual long-term condition and colder for extended holding. Solutions are best split into single-use aliquots and frozen; the factors that set a peptide's usable life are covered in how long peptides last.
• Identity. The monoisotopic mass distinguishes intact VIP from the sulfoxide, from deamidated forms (+1 Da) and from deletion sequences. Because a 28-mer is long enough for a single-residue deletion to be hard to see by reversed-phase chromatography, mass confirmation matters more here than for a short peptide; the distinction between a peptide and a small protein of this size is discussed in peptides vs proteins.