VIP-based gut hormone research peptide (CHEMBL3102919)
A lab-made, chemically stabilized copy of VIP, a natural gut and nerve hormone; used only as a research tool to help design new peptide drugs.
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 is a 30-residue research peptide called I17-VIP-GK (catalogued as CHEMBL3102919). It is a small chemical edit of vasoactive intestinal peptide (VIP) — the natural 28-amino-acid gut/neural hormone first isolated from porcine intestine in 1970 (Said and Mutt, Science 1970). Two changes were made to the parent VIP sequence: the methionine at position 17 was swapped for isoleucine (M17I, to remove an oxidation-prone residue), and the C-terminus was extended by glycine-lysine (GK). The result is a peptide that retains VIP's potency at the VPAC2 receptor while being more chemically stable and easier to use as a starting point for further analog design. It is not a clinical drug — it is a medicinal-chemistry reference compound (Giordanetto and colleagues, ACS Medicinal Chemistry Letters 2013).
The stored sequence HSDAVFTDNYTRLRKQIAVKKYLNSILNGK contains the M17I substitution (the "I" at position 17) and the C-terminal GK extension; in the source paper this peptide is the unstapled parent reference (compound 1) against which all stapled analogs were benchmarked. No N-terminal cap, C-terminal amidation, lipidation, or staple is present in this 30-mer — those modifications appear in the derivative compounds, not in the parent.
History
VIP itself was discovered by Sami Said and Viktor Mutt at the Karolinska Institute, who isolated it from porcine duodenal extracts based on its potent vasodilator activity (Said and Mutt, Science 1970). VIP was subsequently shown to act through two related class B G-protein-coupled receptors — VPAC1 and VPAC2 — which have distinct tissue distributions and physiological roles.
By the late 1990s and 2000s, VPAC2 agonism emerged as a candidate mechanism for type-2 diabetes because activation of VPAC2 on pancreatic β-cells enhances glucose-dependent insulin secretion, while activation of VPAC1 (expressed on hepatocytes and elsewhere) promotes hepatic glucose production — a metabolically opposing effect. A potent VPAC2-selective agonist would, in principle, boost insulin only when blood glucose is high, without the VPAC1-mediated downside (Tsutsumi and colleagues, Diabetes 2002).
I17-VIP-GK was constructed by Giordanetto and colleagues at AstraZeneca as the unmodified reference compound for a stapled-peptide campaign aimed at improving VPAC2 agonism, protease resistance, and membrane permeability (ACS Medicinal Chemistry Letters 2013). The C-terminal GK extension was added because, by analogy with the receptor-bound conformation of GIP, the extra residues neutralise the helix macrodipole and provide helix-capping hydrogen bonds, stabilising the bioactive C-terminal helix.
What it does
In cell-based assays, I17-VIP-GK activates the VPAC2 receptor with low-picomolar potency. Giordanetto and colleagues (2013) reported a VPAC2 EC50 of 0.14 ± 0.09 nM — essentially indistinguishable from native VIP (0.19 ± 0.04 nM) in the same assay. VPAC1 activity was not measured in that paper, so any platform metadata listing VPAC1 EC50 = 0.14 nM should be read as inheriting the VPAC2 value from the underlying ChEMBL record.
Functionally, VPAC2 agonists like this one work by binding the VPAC2 receptor on pancreatic β-cells. The receptor is a class B GPCR that signals through Gαs, raising intracellular cAMP and amplifying glucose-stimulated insulin release. Because the downstream insulin response still requires elevated blood glucose to fire, the effect is glucose-dependent — insulin output rises when it is needed, not when blood sugar is low (Pirot and colleagues, Frontiers in Endocrinology 2022; Bourgault and colleagues review).
Evidence
- In vitro: VPAC2 EC50 = 0.14 ± 0.09 nM in a cAMP accumulation assay; compared to native VIP at 0.19 ± 0.04 nM in the same assay (Giordanetto, ACS Med Chem Lett 2013). The molecule's primary use in the literature is as the parent/reference compound in a stapled-VIP medicinal-chemistry series; the stapled derivatives went on to show improved potency, helicity, and protease stability.
- Animal: No published in vivo data specifically on I17-VIP-GK as a standalone agent. The broader class of VPAC2-selective VIP analogs has been studied in rodent glucose-tolerance models (Tsutsumi 2002; Pan and colleagues, J Pharmacol Exp Ther 2007).
- Human: No clinical trials. This is a discovery-stage research peptide, not a drug candidate that progressed to human dosing.
Known effects
- VPAC2 receptor activation — Confirmed in vitro at low-picomolar EC50 (Giordanetto 2013).
- Glucose-dependent insulin secretion (class effect) — Demonstrated for VPAC2 agonists generally; not specifically reported in vivo for I17-VIP-GK itself.
Regulatory status
- US / EU: Not a drug. No FDA or EMA submissions; the peptide exists only in the medicinal-chemistry literature and in the ChEMBL bioactivity database (entry CHEMBL3102919).
- WADA: Not specifically listed. VIP and analogs are not on the current WADA Prohibited List as a named class.
Related peptides
- Vasoactive intestinal peptide (VIP, 28-mer) — the parent endogenous hormone. I17-VIP-GK differs from VIP only by M17I and the GK extension.
- PACAP (pituitary adenylate cyclase-activating polypeptide) — the other endogenous ligand for VPAC1 and VPAC2, sharing the same receptor family.
- Stapled VIP analogs from Giordanetto 2013 — olefin-stapled and lactam-bridged derivatives of this peptide form the rest of the series that I17-VIP-GK anchors.
Open questions
- Selectivity over VPAC1 was not measured in the source paper; the VPAC1/VPAC2 selectivity ratio for this exact 30-mer is therefore unknown from the primary literature cited here.
- No proteolytic-stability data are reported for the unstapled parent in the 2013 paper — the stability story belongs to the stapled derivatives, not to this molecule.
- No structural data (NMR, X-ray, cryo-EM) specifically of I17-VIP-GK bound to VPAC2 have been published.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| EC50 | 0.14 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.830 | global PDE — lower = better |
| disorder | 0.191 | fraction disordered |
| chain pair ipTM (A, B) | 0.825 | 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 | 412s |
| 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{pep10474,
sequence = {HSDAVFTDNYTRLRKQIAVKKYLNSILNGK},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}