VIP receptor-1 research tool: modified VIP peptide (Ala11,22,28-VIP)
A lab-made version of VIP, a natural gut-and-brain signaling molecule, tweaked to activate only one of VIP's two receptors; 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.
Named peptide fragment — synthesized for research; ClinicalTrials.gov trials registered for parent compound or class
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Endogenous peptide fragment — receptor binding/activity established in published literature; CT.gov evidence
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What this is
(Ala11,22,28)-VIP is a synthetic, slightly modified version of vasoactive intestinal peptide (VIP), a 28-amino-acid neuropeptide that the body naturally produces in the gut, brain, lungs, and immune system. The modification — swapping three amino acids (positions 11, 22, and 28) for alanine — gives the analog roughly 1,000-fold selectivity for one of VIP's two receptors, VPAC1, over the other (VPAC2). This makes it a pharmacological tool for isolating VPAC1-specific biology without simultaneously activating VPAC2. The stored sequence (HSDAVFTDNYARLRKQMAVKKALNSILA, 28 residues) represents the backbone; like native VIP, the active form carries a C-terminal amide (-NH₂) that is not visible in the raw sequence. The parent peptide VIP itself — whose synthetic pharmaceutical form is called aviptadil — is not FDA- or EMA-approved for any indication.
History
VIP was isolated in 1970 by Sami Said and Viktor Mutt at the Karolinska Institute in Stockholm from porcine intestinal tissue during a program to characterize gastrointestinal hormones, named for its potent vasodilatory activity. The two receptor subtypes, VPAC1 and VPAC2, were cloned in the 1990s, establishing the framework for receptor-selective pharmacology. A complete alanine scan of VIP — systematically replacing each residue with alanine and measuring the effect on receptor binding and activation — identified positions 11 (Thr), 22 (Tyr), and 28 (Asn) as critical for VPAC2 selectivity while sparing VPAC1 binding, enabling the design of (Ala11,22,28)-VIP as a selective VPAC1 agonist tool compound (Couvineau and Laburthe, British Journal of Pharmacology 2012). Structure-function work using photoaffinity labeling confirmed that VIP's C-terminal α-helix (residues 7–28) is accommodated by the VPAC1 N-terminal ectodomain, while the disordered N-terminus (residues 1–5) contacts the receptor transmembrane domain to trigger activation. Aviptadil (synthetic VIP) was designated an International Nonproprietary Name by the WHO in 1997.
What it does
(Ala11,22,28)-VIP activates VPAC1 receptors with minimal engagement of VPAC2, making it useful for studying VPAC1-specific biology in tissues where both receptor subtypes are co-expressed. Through VPAC1, it engages the same downstream signaling as native VIP — coupling to the Gs protein to raise intracellular cAMP — but the receptor-subtype selectivity allows researchers to parse which of VIP's many biological effects are VPAC1-driven versus VPAC2-driven. The parent peptide VIP produces vasodilation, bronchodilation, intestinal secretion, anti-inflammatory cytokine suppression, and neuroprotective effects; (Ala11,22,28)-VIP is primarily deployed as a research tool to attribute these effects to specific receptor subtypes rather than as a therapeutic agent in its own right.
Evidence
- Molecular pharmacology (VPAC1 structure-function and analog design): Couvineau and Laburthe (British Journal of Pharmacology, 2012) reviewed structure-activity data from directed mutagenesis, photoaffinity labeling, NMR, and molecular modeling of VPAC1. The complete alanine scan of VIP identified a diffuse pharmacophore and established that substituting alanine at positions 11, 22, and 28 confers approximately 1,000-fold selectivity for VPAC1 over VPAC2, yielding (Ala11,22,28)-VIP. VIP contacts the VPAC1 N-terminal ectodomain at residues Asp107, Gly116, Cys122, and Lys127 via VIP side chains at positions Phe6, Tyr22, Asn24, and Asn28. The VPAC1 N-terminal ectodomain is structured as a Sushi domain with two antiparallel β-sheets stabilized by three disulfide bonds. Animal models of chronic inflammatory diseases including lung inflammation, colitis, rheumatoid arthritis, septic shock, encephalomyelitis, and hepatitis showed consistent anti-inflammatory effects of exogenous VIP in that review.
- Animal (VIP in stress-induced intestinal motility): Yakabi and colleagues (American Journal of Physiology Gastrointestinal and Liver Physiology, 2018) studied VIP's role in stress-driven colonic motor function in rats. Using a VIP receptor antagonist ([4Cl-D-Phe6,Leu17]VIP, 250 μg/kg intraperitoneally), the authors completely prevented corticotropin-releasing factor-induced fecal output (2.5±0.8 vs 8.5±1.0 pellets/h) and diarrhea. Double immunolabeling showed that 93.4% of VIP-positive neurons in the ileal submucosal plexus were activated by CRF, and CRF-induced colonic c-Fos expression was reduced by 71–80% when VIP signaling was blocked. These data established VIP as the primary downstream effector of stress-related intestinal motility.
- Human (aviptadil inhalation in pulmonary hypertension, n=20): Leuchte and colleagues (European Respiratory Journal, 2008) tested a single 100-μg inhaled aviptadil dose during right-heart catheterization in 20 patients with pulmonary hypertension (PAH n=9, PH with chronic lung disease n=8, chronic thromboembolic PH n=3). Aviptadil produced a significant temporary reduction in mean pulmonary arterial pressure (−1.7 mmHg, P<0.05 immediately post-inhalation), a maximum pulmonary vascular resistance reduction of −1.0 Wood units (P<0.001), and significant increases in stroke volume, cardiac output, and mixed venous oxygen saturation. Systemic arterial pressure was not significantly affected, consistent with pulmonary selectivity of the inhaled route. Six patients (30%) achieved PVR reduction >20%. In patients with chronic lung disease, arterial oxygen tension improved by 4.9 mmHg (P<0.05). Aviptadil was well tolerated with no treatment-related adverse events in 19 of 20 patients.
- Human (VIP physiology and GI pathophysiology): Iwasaki and colleagues (F1000Research, 2019) reviewed VIP's physiological and pathological roles across the gastrointestinal system, including its regulation of ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms, drawing in part on genetic ablation models.
- Human (VIP axis in inflammatory and autoimmune disease): Martínez and colleagues (International Journal of Molecular Sciences, 2019) reviewed the clinical approach to VIP-axis-based therapy in inflammatory and autoimmune diseases, including rheumatoid arthritis, lupus, and Sjögren syndrome, covering VPAC1 and VPAC2 receptor pharmacology in immune cells.
Myths and misconceptions
- "VIP is simply a gut hormone" — VIP is a neuropeptide of the enteric, peripheral, and central nervous systems, as well as an immune mediator. While isolated from intestinal tissue, VIP is expressed in CNS neurons, immune cells, the respiratory tract, and the cardiovascular system; it is not a classical endocrine hormone secreted by gut epithelial cells.
- "VIP and PACAP are the same peptide" — VIP and PACAP are distinct peptides that share VPAC1 and VPAC2 receptors but differ in sequence length (VIP 28 aa, PACAP 38 aa) and receptor selectivity: PACAP also binds PAC1R at high affinity, which VIP does not. Their biological profiles and therapeutic contexts differ accordingly.
- "Aviptadil (synthetic VIP) is approved for COVID-19 or pulmonary hypertension" — Aviptadil has not received FDA or EMA approval for any indication. Multiple randomized controlled trials in COVID-19-associated respiratory failure were conducted (2020–2022); the FDA declined Emergency Use Authorization in 2021, and subsequent trial data including the TESICO trial did not support clear efficacy. Early-phase data in pulmonary hypertension support the VIP-deficiency hypothesis but no approved therapy exists as of this writing.
Common questions
What makes (Ala11,22,28)-VIP different from VIP itself? The three alanine substitutions (at positions 11, 22, and 28) disrupt the specific contacts that native VIP uses to bind and activate the VPAC2 receptor, while preserving VPAC1 binding and activation. The result is approximately 1,000-fold selectivity for VPAC1 over VPAC2, making the analog a tool for experiments that need to isolate VPAC1-specific effects in tissues where both receptors are present (Couvineau and Laburthe, British Journal of Pharmacology, 2012).
Why is VIP deficient in idiopathic pulmonary arterial hypertension? Patients with idiopathic PAH have reduced circulating VIP levels and compensatorily upregulated VPAC receptor expression in the pulmonary vasculature. VIP normally maintains pulmonary vascular tone through VPAC1/VPAC2 → cAMP → PKA-mediated smooth muscle relaxation, and acts as an anti-proliferative factor in pulmonary vascular cells. The Leuchte and colleagues 2008 study demonstrated that inhaled aviptadil substitution produces acute, pulmonary-selective vasodilation in these patients.
How does VIP modulate inflammation without causing broad immunosuppression? VIP acts primarily through VPAC1 on macrophages, dendritic cells, and T cells to suppress NF-κB activation and reduce pro-inflammatory cytokine output (TNF-α, IL-6, IL-12), while promoting regulatory T-cell activity and shifting the Th1/Th2 balance. This is receptor-mediated at tissue concentrations and appears immunomodulatory rather than broadly immunosuppressive — though VIP-knockout and VPAC1-knockout mouse data indicate a bidirectional relationship: endogenous VIP can also be permissive for certain inflammatory responses.
Known effects
- Selective VPAC1 agonism — primary pharmacological property of (Ala11,22,28)-VIP; ~1,000-fold selectivity for VPAC1 over VPAC2 (Couvineau and Laburthe, 2012); used as research tool
- Vasodilation (pulmonary and systemic, via parent VIP/aviptadil) — VPAC1/VPAC2 → cAMP → smooth muscle relaxation; inhaled aviptadil demonstrated pulmonary selectivity in PAH patients (Leuchte and colleagues, 2008)
- Bronchodilation — VIP pharmacology; clinical data from inhaled administration limited
- Intestinal secretion and motility modulation — VIP released from submucosal plexus neurons drives intestinal secretomotor responses; VIP antagonism blocks stress-induced diarrhea in rats (Yakabi and colleagues, 2018)
- Anti-inflammatory (suppression of Th1/NF-κB/TNF-α) — demonstrated in multiple rodent inflammatory disease models; mechanism via VPAC1 on macrophages and T cells (Smalley and colleagues, Clinical and Experimental Immunology, 2009)
- Neuroprotection (indirect) — VIP stimulates astroglia to release ADNF and ADNP, preventing neuronal apoptosis in rodent models; inhibits microglial TNF-α and IL-1β in Parkinson's disease models
- Immunomodulation — modulates NK cells, dendritic cells, and T-cell subsets; classified as a cytokine-like peptide in the immune compartment
Safety signals
No systematic human safety database exists from regulatory-standard trials for VIP, aviptadil, or the (Ala11,22,28)-VIP analog. In the Leuchte and colleagues 2008 inhalation study (n=20), aviptadil was well tolerated with no treatment-related adverse events at 100 μg inhaled; systemic blood pressure was unaffected, consistent with pulmonary selectivity of the inhaled route. Higher doses or systemic administration would be expected to cause hypotension and diarrhea based on VIP's vasodilatory and intestinal-secretory pharmacology. The short plasma half-life of native VIP (minutes), driven by rapid cleavage of the N-terminal His-Ser dipeptide by dipeptidyl peptidase IV (DPPIV), limits systemic exposure with non-IV routes. (Ala11,22,28)-VIP is a research-grade tool compound; no human safety dataset is available for the analog specifically.
Regulatory status
- US: Not approved. Aviptadil has been investigated under FDA IND. No NDA or BLA approval for any indication.
- EU: Not approved. EMA has not granted marketing authorization for aviptadil for any indication.
- WADA: VIP is not listed on the WADA prohibited substance list. It is a naturally occurring neuropeptide and not classified as a prohibited peptide hormone or growth factor.
Related peptides
See also: Sermorelin, Glucagon
Mechanism
(Ala11,22,28)-VIP binds selectively to VPAC1, the primary receptor subtype expressed on immune cells (macrophages, dendritic cells, T cells), intestinal submucosal neurons, and lung epithelium. The selectivity is the functional difference from native VIP; the downstream signaling through VPAC1 is the same.
Structural basis of VPAC1 binding: VIP adopts an α-helical conformation in residues 7–28 when bound to receptor, while the N-terminal 1–5 segment is disordered in solution. The 'two-domain' binding model (Couvineau and Laburthe, British Journal of Pharmacology, 2012) describes VIP's C-terminal α-helix being captured by the VPAC1 N-terminal ectodomain (N-ted), a Sushi-domain fold stabilized by three disulfide bonds (Cys50-Cys72, Cys63-Cys105, Cys86-Cys122), which orients the disordered N-terminus toward the transmembrane domain for receptor activation. The three alanine substitutions in (Ala11,22,28)-VIP eliminate side-chain contacts at positions 22 and 28 that native VIP uses to engage VPAC2 without comparably disrupting VPAC1 N-ted contacts.
VPAC1 → Gαs → cAMP signaling: VPAC1 is a class B GPCR that couples to Gαs, activating adenylyl cyclase and raising intracellular cAMP, which activates PKA. Downstream consequences depend on cell type:
- In smooth muscle (pulmonary, bronchial, vascular): PKA phosphorylates myosin light chain kinase → relaxation → vasodilation and bronchodilation
- In intestinal submucosal secretomotor neurons: drives water and electrolyte secretion from intestinal epithelium and regulates the peristaltic reflex
- In immune cells (macrophages, dendritic cells, T cells): cAMP → PKA → inhibition of NF-κB → reduced TNF-α, IL-6, IL-12; promotion of Th2 and regulatory T-cell phenotypes
VPAC1 accessory protein interactions: VPAC1 interacts with RAMP2 (receptor activity-modifying protein 2), producing selective enhancement of IP3 production and intracellular Ca²⁺ mobilization without affecting cAMP coupling — a parallel signaling pathway relevant in specific cellular contexts. VPAC1 also associates with the PDZ-domain protein MAGI-2/S-SCAM (recruiting it to apical lateral junctions in epithelial cells) and with calmodulin via the C-terminal tail.
Neuroprotective mechanism: VIP stimulates astroglia to release activity-dependent neurotrophic factor (ADNF) and ADNP — femtomolar-active neuroprotective proteins of the heat shock family — which prevent neuronal apoptosis. VIP also inhibits microglial TNF-α and IL-1β secretion, attenuating neuroinflammation in rodent Parkinson's disease models. These indirect neuroprotective effects distinguish VIP from classical neurotrophins.
VIP degradation: The parent peptide VIP is susceptible to rapid proteolysis by DPPIV, which cleaves the N-terminal His-Ser dipeptide and eliminates VPAC receptor affinity. This short plasma half-life (minutes in systemic circulation) is the primary pharmacological limitation of native VIP as a systemic therapeutic, motivating the aerosol aviptadil formulation (direct pulmonary delivery avoiding first-pass systemic proteolysis) and driving interest in DPPIV-resistant analogs.
Open questions
- Whether selective VPAC1 agonists such as (Ala11,22,28)-VIP can be developed into small-molecule (non-peptide) drugs with therapeutic utility in inflammatory disease — no satisfactory non-peptide VPAC1 modulator currently exists
- The bidirectional role of VIP in inflammation: VIP administration is anti-inflammatory in most rodent models, but VIP-knockout and VPAC1-knockout mice show partial resistance to experimental colitis and encephalomyelitis, suggesting endogenous VIP can also be permissive for certain inflammatory contexts; reconciling these findings for therapeutic targeting remains unresolved
- Whether chronic inhaled aviptadil provides clinically meaningful hemodynamic and functional benefit in PAH beyond the acute single-dose effects observed by Leuchte and colleagues (2008) — adequate chronic-dosing trial data have not been published
- The pharmacokinetics of inhaled aviptadil in terms of local airway versus systemic VIP levels, duration of pulmonary action, and optimal dosing frequency
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8498839735984802 | openfold3-mlx |
| ranking score | 0.9226029515266418 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.790 | global PDE — lower = better |
| disorder | 0.202 | fraction disordered |
| chain pair ipTM (A, B) | 0.850 | 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{pep10583,
sequence = {HSDAVFTDNYARLRKQMAVKKALNSILA},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}