VIP nerve messenger peptide
The guinea pig form of a natural signaling molecule found in the gut, lungs, and brain that calms inflammation and relaxes muscle; used only 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
This card holds the guinea pig form of vasoactive intestinal peptide (VIP) — a 28-amino-acid messenger that bodies make naturally in the gut, lungs, brain, and immune tissue. VIP itself was first purified from porcine intestine in the 1970s, and the guinea pig sequence stored here (HSDALFTDTYTRLRKQMAMKKYLNSVLN) was characterized later as part of a cross-species comparison alongside the dog and goat orthologs (Eng 1986). VIP's main job is to dial down inflammation and relax smooth muscle, and it does that by binding to two closely related receptors, VPAC1 and VPAC2 (Couvineau 2012). Storing the guinea pig variant is useful because it lets researchers probe VPAC1 biology with the exact sequence used in classic comparative pharmacology experiments.
History
VIP was originally isolated by Sami Said and Viktor Mutt at the Karolinska Institute in Stockholm, working from porcine small intestine, and was named for the potent vasodilator activity that first drew attention to it. Comparative work in the 1980s established that VIP sequences across mammals are highly conserved but not identical — Eng and colleagues (1986) purified and sequenced the dog, goat, and guinea pig peptides and showed where each diverges from the porcine reference. That cross-species work is the source of the guinea pig sequence held on this card. Over the following decades, VIP biology widened to include immune modulation, regulation of gut motility and secretion, smooth-muscle relaxation in the airways and vasculature, and circadian signaling — making it one of the most broadly studied gut–brain peptides (Iwasaki 2019).
What it does
In the body, VIP behaves like a brake on inflammation and a relaxant for smooth muscle. Released from nerves and immune cells, it tells blood vessels to dilate, airways to open, and immune cells to tone down pro-inflammatory signaling (Smalley 2009). In the gut, it is one of the principal neurotransmitters of the so-called nonadrenergic, noncholinergic (NANC) inhibitory innervation — the nerve circuits that relax sphincters, slow contractions, and coordinate secretion (Venugopalan 1989). It also helps regulate fluid and electrolyte secretion across intestinal epithelium and plays a role in mucosal defense (Iwasaki 2019; Grondin 2020). Because the same receptors are expressed on T cells, macrophages, and dendritic cells, VIP doubles as an endogenous immune modulator that shifts cytokine balance away from pro-inflammatory and toward regulatory profiles (Smalley 2009).
Mechanism
VIP acts through two class B G-protein-coupled receptors, VPAC1 and VPAC2, both of which couple primarily to Gs and raise intracellular cAMP on activation (Couvineau 2012). The card's stored target is VPAC1, which is the more widely expressed of the two — notable on intestinal epithelium, T cells, macrophages, and lung tissue — while VPAC2 dominates in smooth muscle, the suprachiasmatic nucleus, and certain immune subsets (Couvineau 2012). Through cAMP-dependent signaling, VIP relaxes vascular and airway smooth muscle, suppresses production of pro-inflammatory cytokines, and promotes anti-inflammatory and regulatory cell phenotypes (Smalley 2009). The guinea pig sequence shown here differs from human VIP at a small number of positions but retains the full 28-residue length and the receptor-engaging core, which is why it has been used historically as a comparative tool in receptor pharmacology (Eng 1986).
Evidence
- Human: Most clinical evidence comes from the synthetic VIP analog aviptadil rather than the guinea pig sequence itself; trials in pulmonary arterial hypertension and in COVID-19-related acute respiratory distress have produced mixed results, and translation of strong mechanistic rationale into proven therapy has remained difficult (Iwasaki 2019).
- Animal: Extensive preclinical work across colitis, arthritis, and pulmonary inflammation models, including studies of colonic VIP delivery via nanomedicine that alleviated colitis in rodent models (Jayawardena 2020).
- In vitro: VPAC1 and VPAC2 pharmacology — receptor binding, cAMP responses, accessory-protein interactions — is well characterized in cell-based assays and informs nearly all downstream VIP biology (Couvineau 2012).
Known effects
- Smooth-muscle relaxation (vasodilation, bronchodilation) — well-established pharmacology (Couvineau 2012; Iwasaki 2019)
- Anti-inflammatory and immune modulation — extensive preclinical and mechanistic data (Smalley 2009)
- NANC inhibitory neurotransmission in the gut — classic physiology (Venugopalan 1989)
- Mucosal and epithelial regulation in the GI tract — preclinical and translational evidence (Iwasaki 2019; Grondin 2020)
- Modulation of joint inflammation via VPAC receptors — studied in rheumatoid arthritis contexts (Gomariz 2019)
- Cutaneous thermoregulatory vasodilation — VIP is one of the neurotransmitters implicated in active vasodilation in human skin (Kellogg 2010)
Safety signals
VIP's most predictable acute effect is hemodynamic: at pharmacologic exposures it is a potent vasodilator and can lower blood pressure (Couvineau 2012; Iwasaki 2019). Aviptadil clinical trials in critically ill COVID-19 patients reported the kinds of adverse events expected from a vasoactive infusion in that population, and the FDA declined Emergency Use Authorization for intravenous aviptadil in 2021. Subsequent randomized trials, including the TESICO trial, did not establish efficacy in COVID-19-associated respiratory failure (Iwasaki 2019 covers the broader VIP context; specific TESICO data lies outside this card's references). Beyond hemodynamics, native VIP has a very short plasma half-life and is rapidly degraded — which is one reason most therapeutic development has focused on stabilized analogs rather than the bare 28-residue peptide.
Regulatory status
- US: VIP is not FDA-approved for any indication. The synthetic VIP analog aviptadil was investigated for COVID-19-related acute respiratory distress syndrome; the FDA declined Emergency Use Authorization for intravenous aviptadil in 2021.
- EU / other: No major regulatory authority has approved VIP or aviptadil for general therapeutic use as of this writing.
- Status of this card: the stored sequence is the guinea pig species variant; it is a research/comparative-pharmacology reagent rather than a marketed drug product.
Open questions
- Whether the guinea pig sequence differs measurably from human VIP in VPAC1 versus VPAC2 selectivity or potency in head-to-head modern assays — classic comparative work establishes the sequences but does not exhaustively map cross-species receptor pharmacology (Eng 1986; Couvineau 2012).
- How well preclinical immune-modulation findings translate to disease-modifying outcomes in humans — strong mechanism has not yet produced approved therapies (Smalley 2009; Iwasaki 2019).
- Whether stabilized analogs, alternate routes (inhaled, colonic, nanoparticle-formulated), or receptor-subtype-selective ligands can deliver VIP's pharmacology without its dose-limiting hypotension (Jayawardena 2020).
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.
If natural VIP makes sepsis worse by dropping blood pressure too fast, could a gentler, slower version still fight inflammation safely?
If true, doctors might gain a new way to calm the immune storm in sepsis without the deadly side effect of crashing blood pressure. This could save lives in intensive care units where current treatments often fail.
If the VIP nerve signal is missing in ulcerative colitis, could putting it back help rebuild the protective mucus layer?
If true, patients with ulcerative colitis might have a new treatment option that repairs the gut lining rather than just suppressing inflammation. This could mean fewer flares and less need for surgery over time.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8477578163146973 | openfold3-mlx |
| ranking score | 0.9242812395095825 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.792 | global PDE — lower = better |
| disorder | 0.208 | fraction disordered |
| chain pair ipTM (A, B) | 0.848 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 408s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10582,
sequence = {HSDALFTDTYTRLRKQMAMKKYLNSVLN},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}