Vasoactive intestinal peptide (VIP): natural nerve and immune messenger
A signaling molecule made naturally in nerves, gut, and immune cells that relaxes airways, aids digestion, and helps regulate the immune system and the brain's internal clock; used as a lab research tool.
- Class
- Neuropeptide / vasoactive peptide (rat-derived variant)
- Status
- No approved therapeutic status identified in attached sources
- Main caveat
- Source attaches a single 1988 characterization of a structurally distinctive VIP variant isolated from rat basophilic leukemia cells; this is not the canonical human or porcine VIP sequence, and no biological activity, animal efficacy, or human evidence is attached to this card.
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
Vasoactive intestinal peptide (VIP) is a signaling molecule made naturally in the body — in neurons, gut lining cells, and immune cells — that helps coordinate a surprisingly wide range of functions: digestion, immune balance, lung relaxation, hormone release, and the brain's internal clock. It was first isolated from porcine small intestine in 1970, originally identified by its ability to dilate blood vessels (Iwasaki and colleagues 2019). Despite that vascular-sounding name, VIP's reach extends far beyond blood vessels and it is now studied primarily as a neuropeptide and immune regulator. The sequence stored here is the rat-derived 28-amino-acid form, which differs slightly from the human sequence; it has been used extensively to probe VPAC1 receptor binding and signaling in experimental systems (Goetzl and colleagues 1988).
History
VIP was isolated from the small intestine of pigs and reported as a vasodilator in 1970 (Iwasaki and colleagues 2019). Over the following decades it was found not only in the gut but throughout the central and peripheral nervous systems, and in immune cells — establishing it as a genuine neuropeptide with pleiotropic roles. The identification of two distinct receptor subtypes, VPAC1 and VPAC2, clarified why VIP produces such varied effects depending on which tissue expresses which receptor (Couvineau and colleagues 2012). Structural biology advanced substantially with the 2020 cryo-EM structure of the human VIP1 receptor bound to the related peptide PACAP27 and a Gs heterotrimer, providing the first atomic-level view of VIP receptor activation (Duan and colleagues 2020).
What it does
VIP acts on cells by binding to receptors on their surface and triggering a rise in a chemical messenger called cyclic AMP (cAMP) inside the cell. That intracellular signal can relax smooth muscle (producing vasodilation and bronchodilation), stimulate secretion of fluid and enzymes by glands, slow or modulate gut contractions, and instruct immune cells to shift away from inflammatory activity toward tolerance. In the nervous system, VIP-containing interneurons are found in the hippocampus and cortex, where they help synchronize neural circuits and support circadian timekeeping in the brain's master clock, the suprachiasmatic nucleus (Iwasaki and colleagues 2019). In immune tissues, VIP dampens the production of pro-inflammatory cytokines and promotes regulatory immune responses (Martínez and colleagues 2019).
Evidence
- Human: No clinical trials of exogenous VIP have been completed for most indications. Preclinical and mechanistic evidence in autoimmune and inflammatory disease models has motivated interest in VPAC receptor-targeted therapies, with Martínez and colleagues (2019) reviewing the potential clinical application of the VIP axis in inflammatory and autoimmune diseases.
- Animal: VIP protected salivary glands from structural injury and secretory dysfunction in a mouse model of Sjögren syndrome, acting through regulation of the cytokine IL-17A and the water channel protein AQP5 (Li and colleagues 2017). In rodent arthritis models, VPAC receptor signaling has been associated with reduced joint inflammation (Gomariz and colleagues 2019).
- In vitro: The cryo-EM structure of human VIP1R in complex with PACAP27 and Gs heterotrimer, solved in 2020, revealed how class B GPCR activation proceeds for this receptor family and identified structural features relevant to drug discovery (Duan and colleagues 2020).
Known effects
- Vasodilation / smooth muscle relaxation — Established pharmacology; the effect that gave VIP its name (Iwasaki and colleagues 2019)
- Immune modulation (anti-inflammatory) — Preclinical; VIP suppresses pro-inflammatory cytokines and promotes regulatory T-cell responses via VPAC1 and VPAC2 (Martínez and colleagues 2019)
- Exocrine gland regulation — Preclinical and mechanistic; VIP stimulates secretion by gut, salivary, and other exocrine glands (Couvineau and colleagues 2012)
- Gut motility and ion secretion — Preclinical; VIP is an inhibitory motor neurotransmitter in the enteric nervous system, regulating nutrient absorption and ion transport (Iwasaki and colleagues 2019)
- Circadian rhythm entrainment — Preclinical; VIP-expressing neurons in the suprachiasmatic nucleus mediate circadian synchronization (Iwasaki and colleagues 2019)
- Neuroprotection — Mechanistic and rodent models; VIP and its receptors are proposed as targets in neuronal and neurodegenerative contexts (Duan and colleagues 2020)
- Salivary gland protection in Sjögren syndrome model — Preclinical (NOD mice); VIP reduced IL-17A and restored AQP5 expression, protecting secretory function (Li and colleagues 2017)
Safety signals
Safety data for exogenous VIP administration are largely limited to the preclinical literature. As an endogenous peptide with widespread receptor expression, systemic VIP administration carries theoretical effects on blood pressure and heart rate given its vasodilatory pharmacology. No systematic clinical safety dataset for VIP as a standalone therapeutic is available in the dossier.
Mechanism
VIP is a 28-residue peptide that binds to two class B G protein-coupled receptors, VPAC1 and VPAC2, both of which signal primarily through Gαs to raise intracellular cAMP (Couvineau and colleagues 2012). VPAC1 is widely expressed in lymphoid tissue, lung, and gut epithelium; VPAC2 predominates in smooth muscle and brain. cAMP elevation activates downstream kinase cascades that mediate the anti-inflammatory, secretory, and smooth-muscle-relaxing effects observed across tissues. The 2020 cryo-EM structure of human VIP1R bound to PACAP27 and a Gs heterotrimer revealed the receptor's extracellular domain and transmembrane bundle in the active conformation, providing a structural template for future drug design (Duan and colleagues 2020). The rat sequence stored here (HSEAVFTDNYTRLRKQMAVKKYLNSILN) differs from the human sequence at several positions; species differences in VPAC1 recognition have been mapped to non-adjacent amino acid positions in the receptor's extracellular domain (Couvineau and colleagues 2012), which is why rat-derived VIP has been used specifically to interrogate species-selectivity determinants.
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.
Could VIP be dosed precisely enough to fix the brain clock without also causing blood vessels to over-relax?
If true, people with shift-work disorder, jet lag disorders, or psychiatric conditions involving disrupted rhythms could benefit from a targeted treatment that does not carry the blood-pressure risks that have limited VIP-based drugs so far.
Does the low pH found in injured or inflamed tissue chemically alter VIP in a way that stops it from working?
If true, it would explain why VIP-based treatments sometimes fail in real disease, and would guide chemists to build a more acid-stable version that keeps working where the body needs it most.
Does the positively charged stretch in the middle of VIP act as a dial that tunes which of its two main receptors it activates?
If true, drug designers could tweak just a few amino acids to make a VIP-based drug that targets inflammation without disturbing the body clock, or vice versa, reducing unwanted side effects.
Could a short course of VIP treatment around a transplant operation help the immune system accept a new organ without extra toxic drugs?
If true, transplant patients might need lower doses of the powerful immunosuppressants that cause kidney damage and infections, improving long-term survival for people who receive donor organs.
If you cut off the end of VIP, does it stop working on one receptor but keep working on the other?
If true, a shorter version of VIP could be designed that acts mainly on one receptor, potentially making it a more precise drug candidate with fewer side effects for conditions like inflammatory bowel disease or circadian disorders.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8582455515861511 | openfold3-mlx |
| ranking score | 0.9287536144256592 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.768 | global PDE — lower = better |
| disorder | 0.198 | fraction disordered |
| chain pair ipTM (A, B) | 0.858 | 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 | 405s |
| 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{pep10594,
sequence = {HSEAVFTDNYTRLRKQMAVKKYLNSILN},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}