VIP-related nerve-signaling peptide (CHEMBL3102920)
A lab-made cousin of vasoactive intestinal peptide (VIP), a natural signaling molecule in nerves, gut, and immune tissue; 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.
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 30-residue peptide is a close structural relative of vasoactive intestinal peptide (VIP), a naturally occurring signaling molecule found throughout the nervous system, gut, and immune tissues. VIP and related analogs act on two receptors — VPAC1 and VPAC2 — and the compound catalogued here as CHEMBL3102920 was characterized as a VPAC1 ligand with an EC50 of 6.6 nM in a functional adenylyl cyclase assay. It belongs to a series of extended VIP analogs studied to understand how peptide length and sequence modifications affect receptor potency and selectivity. Compared to the 28-amino-acid native VIP sequence, this analog adds a Gly–Lys dipeptide at the C-terminus and carries an isoleucine at position 17 in place of leucine.
What it does
VPAC1 is a class B G protein-coupled receptor (GPCR) that, when activated by VIP-family peptides, couples primarily to the Gs protein and triggers adenylyl cyclase activity, raising intracellular cyclic AMP (cAMP). The cAMP signal then branches into two main downstream channels: the classical protein kinase A (PKA) pathway and the exchange protein activated by cAMP (EPAC) pathway (Giordanetto and colleagues 2013; Bhargava and colleagues, J Mol Recognit 2002). Downstream of PKA, VPAC1 signaling suppresses production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-12, and modulates T-cell differentiation — effects documented extensively for native VIP in animal models of inflammatory disease (Carrión and colleagues, Front Endocrinol 2019). VPAC1 is constitutively expressed on monocytes, macrophages, and T lymphocytes, as well as in intestinal mucosa, lung epithelium, liver, and the central nervous system — a distribution that makes the receptor a target of interest for both immunology and gastroenterology.
Evidence
- In vitro: EC50 = 6.6 nM in a VPAC1 adenylyl cyclase stimulation assay (ChEMBL bioactivity, CHEMBL3102920; associated with Giordanetto and colleagues 2013). Native VIP achieves EC50 values of ~0.1–14 nM at VPAC1 across published assays (IUPHAR/BPS Guide to Pharmacology, VPAC1 receptor entry). The stapled and unstapled VIP derivative series studied by Giordanetto and colleagues showed that the unstapled 30-mer parent compound (I17-VIP-GK, corresponding to this sequence) had EC50 = 0.14 nM at VPAC2; the differential in potency between VPAC1 and VPAC2 for this parent compound is consistent with VIP's known approximately equipotent behavior at both receptor subtypes at low nanomolar concentrations.
- Animal: Native VIP treatment in collagen-induced arthritis models reduced disease incidence, joint swelling, and cartilage destruction, and rebalanced Treg/Th17 ratios — evidence that VPAC1 agonism carries meaningful anti-inflammatory activity in vivo (Carrión and colleagues, Front Endocrinol 2019). VPAC1 null mice develop neonatal intestinal obstruction and hypoglycemia, establishing VPAC1's essential role in gut homeostasis (IUPHAR/BPS receptor data).
- Human: No human clinical data specific to this compound. VIP itself was evaluated in a Phase I trial in acute respiratory distress syndrome and sepsis (NCT00004494). No registered trials on ClinicalTrials.gov for CHEMBL3102920 or the I17-VIP-GK analog.
Known effects
- VPAC1 agonism — In vitro (EC50 6.6 nM; ChEMBL bioassay)
- Adenylyl cyclase stimulation / cAMP elevation — Mechanistic; class effect of VPAC1 agonists (Giordanetto and colleagues 2013)
- Anti-inflammatory signaling — Preclinical (class-level evidence for VIP/VPAC1 axis; Carrión and colleagues, Front Endocrinol 2019)
Mechanism
VPAC1 (encoded by the VIPR1 gene, chromosome 3p22.1) belongs to the class B secretin-family GPCRs. Peptide binding follows a two-site model: the central and C-terminal portions of VIP-family ligands engage the receptor's large N-terminal ectodomain (which contains a "Sushi" fold stabilized by three disulfide bonds), while the N-terminal His–Ser–Asp triad of the peptide inserts into the transmembrane bundle and triggers receptor activation (Laburthe and colleagues, Br J Pharmacol 2012; Ceraudo and colleagues, Biochem Pharmacol 2012). Residues His1, Val5, Arg14, Lys15, Lys21, Leu23, and Ile26 of native VIP are critical contact points for VPAC1 activity; alanine substitutions at these positions cause marked loss of potency (Couvineau and colleagues, J Biol Chem 2000). Gs-coupling to adenylyl cyclase is the primary signaling output, generating cAMP and downstream PKA/EPAC activation. VPAC1 can additionally engage RAMP2, shifting some signaling through phospholipase C and inositol trisphosphate production. The C-terminal GK extension in this 30-mer relative to native VIP is consistent with sequences engineered to accommodate chelator conjugation for radiolabeled imaging probes, as explored in related VIP analog programs.
Open questions
- Whether the 6.6 nM EC50 at VPAC1 reflects a genuine potency difference versus VPAC2 for this specific 30-mer, or an assay-condition artifact, remains unresolved — VPAC2 data for the same assay format are not available in the public record for this compound.
- The C-terminal GK extension's precise functional role (steric accommodation for conjugation vs. direct receptor contact) has not been characterized for the VPAC1 interaction in isolation.
- Proteolytic stability of this 30-mer in serum has not been reported; VIP-class peptides are generally susceptible to DPP-IV cleavage at the His-Ser N-terminal dipeptide.
Related peptides
- Native VIP (28-mer, VPAC1/VPAC2 non-selective agonist; the direct parent sequence from which this 30-mer is derived)
- [Ala11,22,28]VIP — first highly selective (>1,000-fold) VPAC1 agonist derived from VIP by Couvineau and colleagues (J Biol Chem 2000)
- Stapled VIP derivatives studied by Giordanetto and colleagues (ACS Med Chem Lett 2013) — VPAC2-preferring olefin-metathesis stapled analogs built on this same 30-mer scaffold
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| EC50 | 6.6 nM | GPCRDB/ChEMBL |
▸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{pep10475,
sequence = {HSDAVFTDNYTRERKQKAVKKYLNSILNGK},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}