VIP (6-28): lab tool for studying VIP's gut, lung, and immune signaling
A fragment of VIP (the natural body chemical that relaxes muscles and helps regulate the gut and immune system), used in labs to study one specific signaling pathway. Research tool only, not a medicine.
- Class
- Neuropeptide / vasoactive peptide
- Status
- Not approved by any major regulatory authority; aviptadil (synthetic VIP) investigated in multiple RCTs; FDA declined EUA for IV aviptadil in COVID-19 ARDS in 2021
- Best-supported effect
- Anti-inflammatory and immunomodulatory activity in human clinical studies (RA, Graves' disease); pulmonary vasodilation in inhaled pulmonary hypertension trials; aviptadil RCTs in COVID-19 ARDS showed mixed-to-negative results
- Main caveat
- No approved indication exists; the most common off-label use (Shoemaker CIRS protocol) lacks large randomized controlled trial evidence, and the CIRS diagnostic framework itself is contested in mainstream medicine
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 (6-28) is the carboxy-terminal 23-residue fragment of Vasoactive Intestinal Peptide (VIP), covering positions 6 through 28 of the full 28-amino acid sequence. Where the intact VIP acts at both VPAC1 and VPAC2 receptors, the (6-28) fragment is selective for VPAC1 — loss of the five N-terminal residues (His-Ser-Asp-Ala-Val) shifts receptor binding preference toward the VPAC1 subtype (Couvineau and colleagues, British Journal of Pharmacology 2012). Researchers use this fragment as a pharmacological tool to dissect VPAC1-specific signaling from VPAC2-mediated effects in immune, gut, lung, and brain tissue systems.
Full-length VIP itself is a neuropeptide found throughout the human body — gut, lung, central and peripheral nervous system, and immune compartments — first isolated in the early 1970s by Sami Said and Viktor Mutt from porcine intestinal extracts. The (6-28) fragment shares the VIP sequence across human, bovine, porcine, and rat, reflecting the high conservation of VIP across mammals. The stored sequence FTDNYTRLRKQMAVKKYLNSILN is the bare 23-residue backbone; the N-terminal five residues absent from this fragment (His¹-Ser²-Asp³-Ala⁴-Val⁵) are precisely what distinguishes it from the parent peptide and what narrows its receptor selectivity.
History
Full-length VIP was reported as a vasodilator in 1970 and its 28-amino-acid sequence was characterized in the years following by Said and Mutt. The pre-pro-VIP gene structure was described in 1983 (Itoh and colleagues, Nature 1983), placing VIP within a broader precursor peptide family alongside PHM-27. Over subsequent decades, the two VIP receptor subtypes — VPAC1 and VPAC2, both class B GPCRs that signal via adenylate cyclase and cAMP — were cloned and characterized, enabling systematic structure-activity relationship work on VIP fragments and analogs. VIP (6-28) emerged from this receptor pharmacology work as the most-studied truncated fragment for probing VPAC1 selectivity. Despite VIP's well-characterized biology, no approved drug based on VIP or its fragments has reached market. The synthetic VIP analog aviptadil was the primary clinical development vehicle in the 2010s and 2020s and was investigated in multiple randomized trials; the FDA declined Emergency Use Authorization for intravenous aviptadil in COVID-19 ARDS in 2021, and the TESICO trial did not support clear efficacy (Martínez and colleagues, International Journal of Molecular Sciences 2019; Iwasaki and colleagues, F1000Research 2019).
What it does
VIP (6-28) is primarily used as a research reagent rather than as a therapeutic. By engaging VPAC1 selectively, it activates the adenylate cyclase / cAMP pathway in tissues and cell types where VPAC1 predominates — including immune cells, intestinal epithelium, and lung tissue. In this context it reproduces the anti-inflammatory, secretomotor, and vasodilatory effects attributable to VPAC1 signaling, while providing a cleaner pharmacological window than the parent VIP peptide. Couvineau and colleagues reviewed how VPAC1 and VPAC2 differ in tissue distribution, downstream coupling, and interaction with accessory proteins, underscoring the relevance of receptor-selective fragments for mechanistic dissection (British Journal of Pharmacology 2012).
At the level of the parent VIP biology: VIP broadly suppresses pro-inflammatory cytokine production, promotes regulatory T-cell differentiation, acts as a smooth muscle relaxant and bronchodilator in the lung, and functions as a neurotrophic modulator in the nervous system via the activity-dependent neuroprotective protein (ADNP) pathway (Smalley and colleagues, Clinical and Experimental Immunology 2009; Martínez and colleagues, International Journal of Molecular Sciences 2019).
Evidence
- Human: Clinical evidence exists for the parent peptide VIP and its pharmaceutical-grade form aviptadil, not specifically for VIP (6-28) as a human therapeutic. Multiple randomized controlled trials of IV and inhaled aviptadil were conducted for COVID-19-associated ARDS; a systematic review and meta-analysis of aviptadil RCTs has been published, and the TESICO trial (published 2023) did not support efficacy in hypoxaemic respiratory failure. Inhaled VIP showed pulmonary hemodynamic effects in a clinical trial in adults with pulmonary hypertension. Controlled studies examined VIP effects on T-cell subsets and cytokine profiles in rheumatoid arthritis and on VIP-axis markers in Graves' disease; VIP gene polymorphisms have been shown to predict treatment requirements in early RA (Smalley and colleagues 2009; Martínez and colleagues 2019). CIRS-related use (Shoemaker protocol) lacks large randomized controlled trial support and the CIRS diagnostic framework is contested in mainstream medicine.
- Animal: Extensive. Rodent models of colitis, arthritis, lupus, Sjögren syndrome, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and pulmonary hypertension have been studied; preclinical work on VPAC1/VPAC2-selective fragments, including VIP (6-28), has been used to attribute effects to individual receptor subtypes (Couvineau and colleagues 2012; Smalley and colleagues 2009).
- In vitro: VPAC1 and VPAC2 receptor binding, signaling characterization (cAMP assays, adenylate cyclase activation), cytokine modulation, regulatory T-cell induction, and — for VIP — nanomedicine colonic delivery formulation work (Hou and colleagues, Frontiers in Endocrinology 2022; Couvineau and colleagues 2012).
Known effects
- VPAC1-selective receptor agonism — Research use; in vitro and preclinical systems
- Anti-inflammatory cytokine modulation (TNF-α↓, IL-6↓, IL-10↑) — Preclinical; attributed to parent VIP via VPAC1/VPAC2; VPAC1-selective attribution supported by fragment pharmacology work
- Smooth muscle relaxation / bronchodilation — Preclinical and human (parent VIP, inhaled route, pulmonary hypertension trials)
- Regulatory T-cell induction — Preclinical and small human trials (RA)
- Neuroprotective modulation via ADNP pathway — Preclinical only
- Pharmacological tool for VPAC1/VPAC2 mechanistic dissection — Primary established use of this specific fragment
Safety signals
Safety data for VIP (6-28) specifically as an administered compound is not characterized in controlled human studies; the fragment is primarily used as a research tool. Safety signals documented in available literature apply to full-length VIP and aviptadil:
Flushing, mild diarrhea, and nasal congestion have been reported with VIP formulations in clinical use. More consequential is VIP's potent vasodilator effect — hemodynamic signals including hypotension are pharmacologically predictable and reflect VPAC1/VPAC2 activation in vascular smooth muscle. Additive hypotension with nitrates, phosphodiesterase-5 inhibitors, alpha-blockers, and antihypertensives is a pharmacologically predicted concern; source literature identifies this as a genuine hemodynamic risk. VIP is described as contraindicated in hemodynamic instability, severe aortic stenosis, and hypertrophic obstructive cardiomyopathy based on this vasodilatory mechanism. Long-term safety of chronic VIP administration has not been characterized in controlled trials — most available exposure data is acute (infusion or short-course trials); safety of extended daily intranasal or subcutaneous use is essentially uncharacterized in the controlled trial literature (Martínez and colleagues 2019; Smalley and colleagues 2009).
Regulatory status
- US (FDA): Not approved for any indication. The FDA declined Emergency Use Authorization for intravenous aviptadil (synthetic VIP) for COVID-19 ARDS in 2021. Compounded intranasal and injectable VIP has historically been available through 503A compounding pharmacies under individualized prescription for off-label use; the broader peptide compounding regulatory environment is described as tightening.
- EU / UK / Australia: No major regulatory authority has approved VIP or aviptadil for human therapeutic use.
- WADA: Not explicitly listed on the WADA Prohibited List per available sources; however, WADA's S0 category captures substances not approved for human therapeutic use, which covers VIP. Athletes subject to anti-doping rules should verify with their testing authority.
Mechanism
VIP (6-28) binds selectively to VPAC1, a class B G-protein-coupled receptor that signals primarily through Gαs-coupled adenylate cyclase activation and elevation of intracellular cyclic AMP (cAMP). The cAMP-PKA cascade downstream of VPAC1 engagement suppresses production of pro-inflammatory cytokines — including TNF-α, IL-6, and IL-12 — and inhibits NF-κB activation, while promoting anti-inflammatory IL-10 output and regulatory T-cell differentiation. VIP also reduces oxidative stress signaling in preclinical systems.
The selectivity of the (6-28) fragment for VPAC1 over VPAC2 arises from the loss of the five N-terminal residues (His-Ser-Asp-Ala-Val) of full-length VIP. Couvineau and colleagues described VPAC receptor structure, molecular pharmacology, and accessory protein interactions in detail, and the structural basis for differential ligand recognition between VPAC1 and VPAC2 is an active area of study (British Journal of Pharmacology 2012).
Full-length VIP has a plasma half-life of less than one minute, reflecting rapid peptidase degradation. VIP (6-28) as an isolated research fragment shares this susceptibility to proteolytic cleavage and has no modification that would extend its circulation time; it is used primarily in ex vivo and in vitro contexts or in short-window in vivo studies rather than as a systemically administered therapeutic.
In the pulmonary vasculature, VPAC1/VPAC2 activation produces potent vasodilation and bronchodilation — the mechanistic basis for VIP's investigation in pulmonary hypertension and ARDS. In the gut, VIP is part of the nonadrenergic, noncholinergic (NANC) inhibitory innervation system governing smooth muscle relaxation and secretory function, with VPAC1 prominent in intestinal epithelium (Iwasaki and colleagues, F1000Research 2019). In the nervous system, VIP acts as a neurotrophic modulator and influences neuroprotection via the activity-dependent neuroprotective protein (ADNP) pathway.
Open questions
- VPAC1 vs VPAC2 therapeutic attribution: Which effects of full-length VIP in human tissues are mediated primarily by VPAC1 vs VPAC2 remains incompletely resolved in clinical contexts. VIP (6-28)'s value as a research tool depends on the clarity of this separation.
- Translational gap for VIP/aviptadil: Despite well-characterized VPAC1/VPAC2 receptor pharmacology and strong preclinical evidence across multiple disease models, clinical trials of aviptadil did not establish efficacy in COVID-19 ARDS. The mechanistic rationale for many other proposed indications — autoimmune disease, neuroprotection — also rests largely on preclinical data.
- CIRS as a defined indication: No large randomized controlled trial has evaluated VIP specifically for CIRS. The Shoemaker diagnostic framework for biotoxin- and mold-related illness is not accepted in mainstream medicine. Whether VIP produces benefit in this population above protocol background is unresolved.
- Intranasal pharmacokinetics in humans: How much VIP reaches systemic circulation and CNS compartments from an intranasal dose, and with what inter-subject variability, has not been well characterized in controlled studies.
- Long-term safety of chronic administration: Safety of six months or more of daily intranasal or subcutaneous VIP in an outpatient population is essentially uncharacterized in the controlled trial literature.
- Independent replication: A substantial share of COVID-19 aviptadil trial evidence originates from one development program; independent replication of smaller positive signals from autoimmune and pulmonary hypertension trials is a persistent limitation.
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 VIP (6-28) only become structured when it binds its receptor, and could that explain why it binds so tightly?
If the peptide folds as it binds, designing a version that is pre-locked in that shape could create a much more potent and stable drug candidate with a longer shelf life.
Would swapping the two adjacent lysines for arginines help VIP (6-28) resist breakdown and possibly bind the receptor more tightly?
A more stable version of VIP (6-28) could be more useful in longer animal experiments. The binding-affinity gain is plausible but not yet shown, so it would need testing.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9046217203140259 | boltz-2 |
| ranking score | 0.5864405035972595 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10545,
sequence = {FTDNYTRLRKQMAVKKYLNSILN},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}