VIP (Vasoactive Intestinal Peptide): Structure, VPAC Receptor Signaling, and the Preclinical Record — A 2026 Research Guide

Vasoactive intestinal peptide occupies an unusual position in peptide science. Isolated in 1970 from porcine duodenum by Said and Mutt and characterized initially as a gut vasodilator, it spent the following five decades being re-discovered by fields with nothing to do with the intestine — neuroscience, circadian biology, and most recently tumor immunology. Its receptor pharmacology has been resolved to the level of cryo-EM structures, and it is simultaneously one of the least stable peptides a laboratory will ever handle. This guide summarizes the molecular profile, receptor- and pathway-level mechanism, and the published preclinical record as it stands in 2026.

The information below describes in-vitro and preclinical laboratory research only. It is not medical guidance, and none of the findings described here establish safety or efficacy in humans.

Section 1 — Molecular Profile

VIP is a linear 28-residue neuropeptide belonging to the secretin/glucagon superfamily, sharing significant sequence homology with PACAP, secretin, glucagon, and GHRH. It is produced endogenously by neurons of the central and enteric nervous systems and by several immune cell populations, and the synthetic material used in research is a solid-phase-synthesized C-terminally amidated peptide identical to the human sequence.

Key identifiers used in the literature and on analytical documentation:

• Compound name: VIP; vasoactive intestinal peptide; vasoactive intestinal polypeptide; VIP (human, porcine, rat)
• CAS number: 37221-79-7
• Molecular formula: C147H237N43O43S
• Molecular weight: approximately 3,326.8 Da
• Length: 28 amino acid residues, single linear chain, C-terminal amide
• Sequence: 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 (HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2)
• Class: class B GPCR agonist; VPAC1 and VPAC2 receptor ligand
• Structural references: PDB 8E3Z (VPAC1R–VIP–Gs cryo-EM complex); PDB 6VN7 (VIP1R–PACAP27–Gs complex)

Three structural facts matter for anyone working with the molecule. First, the sequence is strongly basic — four lysines and two arginines in a 28-residue chain — which drives significant adsorptive loss to glass and polypropylene surfaces at low working concentrations and is the most common cause of irreproducible dose-response curves in VIP assays. Second, the C-terminal amide is not optional. The free-acid form is a different molecule pharmacologically, and incomplete amidation is a real synthesis failure mode that a purity percentage alone will not reveal; it requires mass confirmation, since the amide and free acid differ by roughly 1 Da.

Third, VIP contains a single methionine at position 17, which is oxidation-prone. Methionine sulfoxide formation is the dominant degradation pathway in improperly stored lyophilized material and in reconstituted stock exposed to air, and it shows up on LC-MS as a +16 Da species. In receptor assays, oxidized VIP is a weaker agonist. This is the specific reason a mass-spectrometric identity check on this compound is more informative than it is for a robust, unmodified peptide.

Regarding stability in biological matrices: VIP is among the shortest-lived bioactive peptides described in the literature, with a reported plasma half-life on the order of one to two minutes, driven by cleavage by dipeptidyl peptidase-IV and neutral endopeptidase (neprilysin, NEP/CD10). Any in-vitro experiment run in serum-containing medium is therefore working with a rapidly declining ligand concentration unless peptidase inhibitors are included — a design consideration that is frequently underestimated and that accounts for a portion of the variance between published cell-culture results.

Section 2 — Mechanism

All activity described here is at the receptor and pathway level, in defined experimental systems.

Receptor engagement. VIP is a high-affinity agonist at two class B (secretin-family) G protein-coupled receptors: VPAC1 (VIPR1) and VPAC2 (VIPR2). It binds both with roughly comparable nanomolar affinity, which is the central pharmacological problem in the field — VIP itself is not a selective tool compound, and separating VPAC1- from VPAC2-mediated events requires selective analogs or receptor-null systems rather than VIP alone. VIP also binds the PAC1 receptor, though with substantially lower affinity than PACAP, its closest structural relative.

Structural basis of binding. The two-domain model that governs class B GPCR activation has been resolved directly for this system. Cryo-EM structures of the VPAC1R–VIP–Gs and VPAC1R–PACAP27–Gs complexes, published in Nature Communications in 2022, showed the peptide C-terminal region engaging the large extracellular domain while the N-terminal residues insert into the transmembrane bundle to drive activation. Molecular dynamics analysis in the same work found notably fewer stable contacts between VPAC1R and VIP than between the receptor and PACAP27, with the VIP–extracellular-loop-3 interaction being conspicuously dynamic. That structural result explains a long-standing observation in the functional literature: VIP behaves as a comparatively “loose” ligand, and small modifications to its N-terminal residues have disproportionate effects on potency.

Canonical signaling. Both VPAC1 and VPAC2 couple principally to Gαs. Receptor activation stimulates adenylate cyclase, raises intracellular cAMP, and activates protein kinase A, which phosphorylates CREB at Ser133 and drives CRE-dependent transcription. cAMP/PKA/CREB is the workhorse readout in VIP receptor assays and the axis against which most antagonist screening is performed. Secondary coupling to Gαq/phospholipase C with downstream calcium mobilization has been described in some cell backgrounds, and the receptors are studied for β-arrestin recruitment and biased signaling as well.

Immune-cell pathway effects. In immune cells, the cAMP/PKA arm converges on transcriptional control of inflammatory gene programs. VIP has been studied in vitro for suppression of NF-κB and, in dendritic cells and macrophages, for shifting cytokine transcription profiles. Work published in 2010 in human T cells characterized the mechanism at the cell-cycle level: VIP applied alongside TCR and CD28 stimulation was reported to arrest progression at the G1/S transition, with reduced cyclin D3 and cyclin E synthesis, maintained p27 levels, and impaired PI3K–Akt signaling. In dendritic cells, VIP exposure has been studied for induction of a tolerogenic phenotype and CCL22 production.

Circadian pathway. VPAC2 has a distinct, well-mapped role in the suprachiasmatic nucleus. Work published in Cell in 2002 using Vipr2-null mice reported failure to sustain circadian rest/activity rhythms and loss of rhythmic expression of the core clock genes mPer1, mPer2, and mCry1, along with the clock-controlled gene AVP. Subsequent slice-imaging studies reported that far fewer SCN cells from Vipr2-null animals expressed detectable rhythms and that those that did were poorly synchronized — placing VPAC2 signaling in the role of a network coupling factor rather than a cell-autonomous clock component.

Throughout the literature these are described as mechanisms VIP has been studied for and researched for — VPAC1/VPAC2 agonism, Gαs-coupled cAMP/PKA/CREB activation, cell-cycle and cytokine transcriptional effects in cultured immune cells, and SCN network coupling in rodent models — not as demonstrated clinical effects in humans.

Section 3 — Preclinical and In-Vitro Research Data

The most active current line of VIP research is, counterintuitively, about blocking the pathway rather than activating it. VIP is characterized in this literature as an immunosuppressive neuropeptide, and several tumor models have reported elevated VIP signaling as a mechanism of T-cell suppression.

In 2024, an International Journal of Molecular Sciences paper described chemical modifications applied to a VIP receptor antagonist (ANT) peptide scaffold to improve its drug-like properties. A follow-on study, published in the Journal of Biological Chemistry in 2025, screened a combinatorial library of VIP antagonist variants by in-silico docking against human VPAC1 and VPAC2 and characterized the resulting high-affinity antagonists. The lead candidate, designated ANT308, was reported to decrease CREB phosphorylation — the canonical downstream readout of VIP receptor signaling — and to increase granzyme B and perforin expression in CD8+ T cells taken from AML patient samples in vitro.

That work carried forward into engineered-cell research. A 2026 Science Translational Medicine paper reported CAR T cells engineered to secrete a VIPR-antagonist peptide (CAR/VIPRa). In preclinical cancer models, the armored cells were reported to retain a memory phenotype and remain metabolically quiescent after manufacture while mounting a strong bioenergetic response upon antigen stimulation, and to recruit host T cells into the antitumor response. Related work in Nature Communications in 2022 reported that targeting VIP-mediated signaling enhanced response to immune checkpoint blockade in preclinical pancreatic ductal adenocarcinoma models.

On the agonist side, the receptor-selective literature is older but methodologically clean. A 2000 alanine-scanning and molecular-modeling study identified the residues governing VIP interaction with human VPAC1 and VPAC2 and produced a highly selective VPAC1 agonist — still one of the standard tool compounds in the field. Work published in 2005 reported that VPAC2 receptor activation, but not VPAC1 activation, reduced loss of skeletal muscle mass and force in rodent atrophy models. Separate 2005 work reported that VIP generated CD4+CD25+ regulatory T cells in vivo in mice, and a 2005 study reported VPAC2-mediated neuroprotection against neonatal excitotoxic brain lesions in mice. Receptor-distribution work published in 2017 mapped VPAC1 expression along the length of the intestine.

What the record does not contain is human outcome evidence generated in this compound’s research-chemical form. The clinical-stage work in this family has proceeded through specific formulated analogs under regulatory oversight, and none of that transfers to a lyophilized research vial.

Section 4 — Published Literature

The following are real, published papers anchoring the VIP record. Researchers should consult the primary sources rather than relying on summaries.

• Said SI, Mutt V (1970). “Polypeptide with broad biological activity: isolation from small intestine.” Science 169(3951):1217–1218. The original isolation and characterization.
• Nicole P, et al. (2000). “Identification of key residues for interaction of vasoactive intestinal peptide with human VPAC1 and VPAC2 receptors and development of a highly selective VPAC1 receptor agonist.” Journal of Biological Chemistry 275(31):24003–24012. PMID 10801840.
• Harmar AJ, et al. (2002). “The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei.” Cell 109(4):497–508. PMID 12086606.
• Delgado M, Chorny A, Gonzalez-Rey E, Ganea D (2005). “Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo.” Journal of Leukocyte Biology. PMID 16204628.
• Anderson P, Gonzalez-Rey E (2010). “Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels.” Molecular and Cellular Biology 30(10):2537–2551. PMID 20231362.
• Duan J, et al. (2020). “Cryo-EM structure of an activated VIP1 receptor–G protein complex revealed by a NanoBiT tethering strategy.” Nature Communications 11:4121. PMC7431577.
• Xu Y, et al. (2022). “A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2.” Nature Communications 13:2272.
• Piper SJ, et al. (2022). “Understanding VPAC receptor family peptide binding and selectivity.” Nature Communications 13:7013. Source of PDB 8E3Z and 8E3Y.
• Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide (2024). International Journal of Molecular Sciences 25(8):4391. PMID 38673976.
• Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity (2025). Journal of Biological Chemistry. PMC13080581. The ANT308 characterization.
• Modulating the VIP–VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models (2026). Science Translational Medicine, DOI 10.1126/scitranslmed.adt9565.

Together these span the original isolation, the receptor pharmacology and selective tool compounds, the structural biology, the circadian genetics, the immune-cell mechanism work, and the current antagonist-directed research front.

Section 5 — Research Applications

In laboratory settings, VIP appears principally as a reference agonist and as a pathway probe. Reported in-vitro applications include use as a positive control for Gαs-coupled cAMP accumulation and CREB phosphorylation assays in VPAC1- or VPAC2-expressing cell lines; as the comparator ligand in VPAC-selective agonist and antagonist screening; as a stimulus in dendritic-cell and T-cell culture models of tolerogenic phenotype induction; as a ligand in radioligand and fluorescence-polarization binding studies; and as a reference peptide in smooth-muscle and epithelial-barrier tissue-bath preparations.

Several handling variables materially affect reproducibility. Because of the basic residue content, adsorptive loss is the leading source of apparent potency drift; low-binding tubes and a carrier protein such as 0.1% BSA in the working buffer are standard countermeasures at nanomolar concentrations. Because Met17 is oxidation-labile, lyophilized material is generally stored at −20°C or below, desiccated and protected from light, with reconstituted stock aliquoted immediately to avoid both freeze-thaw cycling and headspace oxygen exposure. Because peptidase clearance is fast, serum-containing assay media will deplete the ligand over the course of an incubation unless DPP-IV and neprilysin inhibition is designed in.

Endotoxin deserves particular attention here. VIP’s primary research application is immune-cell culture, where the readouts are cytokine transcription, NF-κB activity, and T-cell phenotype — precisely the endpoints endotoxin contamination independently drives. A preparation without a stated endotoxin figure is unsuitable for the work it is most often purchased for, and an unqualified vial can produce a clean-looking but artifactual inflammatory result.

Section 6 — How to Evaluate a Source

For a peptide with an oxidation-labile residue and a mandatory C-terminal amide, the certificate of analysis carries unusual weight. When evaluating any VIP source, confirm:

• Identity by LC-MS, with an observed mass consistent with roughly 3,326.8 Da for the amidated 28-residue peptide. Check that the reported mass corresponds to the amide and not the free acid, and look for a +16 Da methionine-sulfoxide shoulder.
• Purity by HPLC, with a stated percentage and a visible chromatogram rather than a bare number. The oxidized species elutes separately and should be resolvable in a competent method.
• Endotoxin by USP <85> LAL, with an actual figure. Non-negotiable for immune-cell work.
• Heavy metals by ICP-MS.
• Lot-specificity: the COA must correspond to the exact batch shipped, be dated, and name the accredited laboratory that performed the testing.
• Net peptide content, disclosed. Lyophilized basic peptides carry counterion and residual water mass; a vial labeled by gross weight is not the same input as one labeled by net peptide, and the discrepancy can be substantial.

Market pricing context: research-grade VIP is generally listed in 1 mg and 5 mg lyophilized vials, and the per-milligram spread is wide. Synthesizing a 28-residue amidated peptide to high purity is more demanding than producing a short linear sequence, and the cost floor reflects that. A listing well below the prevailing range for this chain length is worth investigating in the analytical data. Price is a poor proxy for quality in either direction; the COA is where the difference becomes visible.

Section 7 — The PYXAX Verification Standard

PYXAX uses accredited independent laboratories in its verification network, including ILS Labs, Krause Analytical, and Janoshik. The current per-batch panel covers purity by HPLC, potency against label claim, and identity by LC-MS. A lot-specific COA is published in the COA Library before dispatch and names the laboratory that tested that batch. Endotoxin, heavy-metals, and final-vial sterility screening are not part of the current panel.

Founding batches are documented end to end, and full analytical data files are available per lot. You can review current documentation in the COA library, read the underlying methodology on the verification standard page, see the VIP listing, or browse the full catalog in the shop.

All PYXAX compounds are supplied strictly for in-vitro and preclinical laboratory research use only. Not for human consumption. Not for veterinary use. Not for diagnostic procedures. These statements have not been evaluated by the FDA. Researchers are responsible for compliance with all applicable laws and regulations governing the use of research compounds in their jurisdiction.