VIP[10-28]: lab fragment of the gut-and-nerve signaling peptide vasoactive intestinal peptide
A shortened piece of vasoactive intestinal peptide (VIP), a natural signaling molecule in the gut, lungs, and nervous system; used in lab research to study how VIP communicates with immune, gut, and brain cells, research tool only.
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
VIP[10-28] is a 19-residue fragment of vasoactive intestinal peptide (VIP) spanning positions 10 through 28 of the full 28-amino acid parent sequence. VIP itself is a well-characterized endogenous neuropeptide produced throughout the gut, nervous system, and immune tissues, belonging to the secretin/glucagon superfamily (Couvineau and colleagues, British Journal of Pharmacology, 2012). The [10-28] fragment retains the C-terminal portion of VIP and is used in laboratory settings to probe VPAC1 receptor function — particularly in immune, gut, lung, and hippocampal preparations — as well as to map the structural features of VIP responsible for receptor binding. This fragment is identical in human, bovine, porcine, and rat VIP, reflecting the high evolutionary conservation of the parent peptide across mammalian species (Wang and colleagues, General and Comparative Endocrinology, 1995).
History
Full-length VIP was isolated from porcine duodenum by Said and Mutt in 1970, purified based on vasodilatory activity, and its complete 28-amino acid sequence was established in 1974. The peptide was subsequently found to be conserved across mammalian species including human, bovine, porcine, and rat. VPAC1 was cloned in 1991 and VPAC2 in 1995 (Couvineau and colleagues, 2012). The [10-28] fragment emerged from structure-activity relationship work designed to understand which portions of VIP are essential for VPAC1 binding and signal transduction. Because the parent peptide shares a conserved N-terminal His-Ser-Asp motif with secretin, glucagon, and PACAP, truncation studies removing the N-terminal segment — leaving the [10-28] C-terminal core — helped investigators isolate the contribution of this region to receptor engagement.
What it does
VIP[10-28] targets the VPAC1 receptor, a class B Gs-coupled GPCR that is broadly expressed in lung, liver, small intestine, brain, and immune cells (Couvineau and colleagues, 2012). VPAC1 activation raises intracellular cAMP and engages PKA signaling downstream. In the context of full VIP biology — from which the [10-28] fragment is derived — this pathway drives smooth muscle relaxation, bronchodilation, intestinal secretion, and suppression of pro-inflammatory cytokine production (Delgado and colleagues, Journal of Molecular Medicine, 2002). In immune cells, cAMP–PKA activation through VPAC1 suppresses TNF-α, IL-6, and IL-12 production while promoting IL-10 and Treg induction (Martínez and colleagues, International Journal of Molecular Sciences, 2019). In the hippocampus, VIP receptor signaling modulates GABAergic transmission and pyramidal cell activity in ways relevant to synaptic plasticity and learning (Cunha-Reis and colleagues, Frontiers in Cellular Neuroscience, 2020). The [10-28] fragment is studied as a tool to interrogate these signaling contexts, particularly for VPAC1-specific effects; its activity relative to full VIP depends on the assay system and receptor expression context.
Evidence
- Human: No human trials have been conducted with the VIP[10-28] fragment itself. Clinical evidence for the VIP axis in humans derives from studies of full-length VIP and its synthetic analog aviptadil — including trials in pulmonary arterial hypertension, COVID-19-associated ARDS, and rheumatoid arthritis (Gomariz and colleagues, Frontiers in Endocrinology, 2019; Martínez and colleagues, 2019).
- Animal: Studies using VIP-family peptides in rodent models of autoimmune disease, colitis, asthma, and pulmonary hypertension have established the pharmacological profile of VPAC1/VPAC2 signaling (Delgado and colleagues, 2002; Iwasaki and colleagues, F1000Research, 2019). Targeted VPAC2 agonism in Parkinson's disease models induces neuroprotective regulatory T cell activity (Mosley and colleagues, Frontiers in Cellular Neuroscience, 2019).
- In vitro: Human macrophages, dendritic cells, and T-cell cultures are the primary systems in which VIP-family peptides have been shown to suppress NF-κB and shift cytokine profiles toward anti-inflammatory phenotypes (Delgado and colleagues, 2002; Martínez and colleagues, 2019). Hippocampal slice preparations have been used to characterize VIP receptor modulation of synaptic plasticity (Cunha-Reis and colleagues, 2020).
Known effects
- VPAC1 receptor activation (Gs-cAMP-PKA pathway) — established for the parent VIP sequence; [10-28] used to map the contribution of this segment
- Anti-inflammatory cytokine modulation (TNF-α suppression, IL-10 induction) via VPAC1 on immune cells — Preclinical
- Regulation of GABAergic and pyramidal cell activity in hippocampus — Preclinical
- Bronchodilation and smooth muscle relaxation — established for full VIP at VPAC1/VPAC2; relevance of [10-28] fragment is assay-dependent
Safety signals
No clinical safety data exist for the isolated VIP[10-28] fragment. From the pharmacology of the parent peptide: VIP and its analogs produce hypotension and tachycardia at intravenous doses due to potent vasodilation — the dose-limiting effect observed in aviptadil trials. The ultrashort plasma half-life of full VIP (under one minute) also applies to fragments that remain susceptible to peptidase cleavage. VIPoma patients — who have endogenous VIP overproduction from islet tumors — develop severe secretory diarrhea, hypokalemia, and hypotension, confirming the pharmacological profile of excess VPAC signaling in humans.
Regulatory status
- US: Not approved for any indication. Research compound.
- EU: Not approved. No EMA submission for this fragment.
- WADA: No explicit restriction. Not a performance-enhancing substance of known concern.
VIP[10-28] is a research tool peptide. Aviptadil — synthetic full-length VIP — has received FDA orphan drug designation for pulmonary arterial hypertension and was investigated for COVID-19-associated ARDS, but has not received approval in any jurisdiction (Martínez and colleagues, 2019).
Related peptides
- Full-length VIP — 28-residue parent peptide; VPAC1/VPAC2 agonist; the source sequence from which [10-28] is derived. The N-terminal 9 residues (HSDAVFTDN) are absent from this fragment.
- PACAP-27 / PACAP-38 — structurally related; activates VPAC1, VPAC2, and PAC1R; neuropeptide with overlapping biology (Couvineau and colleagues, 2012).
- Secretin — same class B GPCR superfamily; N-terminal His-Ser-Asp motif shared with VIP.
- PHM-27 (Peptide Histidine Methionine-27) — co-encoded with VIP from the same precursor gene; weaker VPAC1/VPAC2 agonist.
Mechanism
VIP[10-28] spans residues 10–28 of full human/bovine/porcine/rat VIP (HSDAVFTDNYTRLRKQMAVKKYLNSILN). The fragment's sequence — YTRLRKQMAVKKYLNSILN — comprises the mid-to-C-terminal amphipathic helix of VIP that is critical for receptor contact. Couvineau and colleagues (British Journal of Pharmacology, 2012) describe VPAC1 as a class B Gs-coupled GPCR where the extracellular N-terminal domain engages the C-terminal helix of VIP in the first step of binding, followed by N-terminal VIP engagement of the receptor's transmembrane core — a two-domain interaction model. The [10-28] fragment retains the helical segment and thus engages the VPAC1 extracellular domain, though full activation likely requires the intact N-terminal portion of VIP as well. Upon receptor activation, adenylyl cyclase is stimulated → cAMP rises → PKA is activated. In smooth muscle, PKA phosphorylates myosin light chain kinase (inhibiting contraction) and activates large-conductance K+ channels (hyperpolarizing the cell), producing relaxation and vasodilation. In immune cells, PKA phosphorylates CREB, upregulating IL-10 transcription, while simultaneously reducing NF-κB RelA activity and thereby suppressing TNF-α, IL-6, and IL-12 (Delgado and colleagues, 2002; Martínez and colleagues, 2019). In hippocampal interneurons, VIP receptor–mediated cAMP signaling modulates GABA release and pyramidal cell excitability in a circuit-level mechanism relevant to memory and epilepsy models (Cunha-Reis and colleagues, 2020). The full VIP sequence has a plasma half-life under one minute due to rapid cleavage by dipeptidyl peptidase IV and neutral endopeptidase; the [10-28] fragment, lacking the N-terminal dipeptide that is the primary DPP-IV site, may have a modestly altered degradation profile, though this has not been systematically characterized.
Open questions
- The relative potency and selectivity of VIP[10-28] versus full VIP at VPAC1 has not been systematically characterized across the major tissue systems (immune cells, airway smooth muscle, hippocampal neurons) where VPAC1 signaling is therapeutically relevant
- Whether the C-terminal helical segment alone can drive full cAMP responses in cells expressing only VPAC1 (versus partial agonism or antagonism depending on receptor density) remains to be defined with modern functional assays
- The contribution of endogenous VIP to hippocampal synaptic plasticity and whether VIP-receptor modulation could provide therapeutic benefit in cognitive decline or temporal lobe epilepsy is an active open question (Cunha-Reis and colleagues, 2020)
- Structure-activity studies comparing [10-28] to neighboring truncations ([7-28], [12-28]) across VPAC1 vs. VPAC2 would clarify the minimal pharmacophore — these data are sparse in the literature
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.
Does this fragment of VIP bind to the VPAC1 receptor but fail to fully activate it, effectively acting as a brake on VIP signaling?
A naturally derived VIP antagonist could help treat conditions driven by excess VIP activity, including certain cancers that overexpress VPAC1 and inflammatory diseases where VIP suppresses immune responses too broadly.
Does removing the first nine amino acids of VIP make the remaining fragment more specific to VPAC1 and less active at the closely related VPAC2 receptor?
A VPAC1-selective peptide could help researchers untangle which VIP receptor drives which disease process, and offer a more precise starting point for drugs targeting inflammatory or neurodegenerative conditions.
Could this shorter form of VIP block the signal that some cancers use to suppress immune cells, potentially helping the immune system attack tumors?
If this hypothesis holds, VIP[10-28] analogs could become a new class of immune-checkpoint agents targeting a pathway currently untouched by approved cancer immunotherapies.
Do the multiple positively charged amino acids in VIP[10-28] cause it to concentrate on the negatively charged outer surface of cells, putting it close to its receptor?
If this membrane-anchoring effect is real, it could explain why this short fragment works in tissues and point toward designing VIP-based therapies that are more potent at lower doses.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7842380404472351 | openfold3-mlx |
| ranking score | 0.8552179932594299 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.782 | global PDE — lower = better |
| disorder | 0.183 | fraction disordered |
| chain pair ipTM (A, B) | 0.784 | 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 | 389s |
| 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{pep10719,
sequence = {YTRLRKQMAVKKYLNSILN},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}