pe
pep-10469 v1 CC-BY-SA-4.0

Experimental peptide targeting a VIP receptor (CHEMBL3884667)

A lab-made peptide designed to act on a receptor involved in gut, nerve, and immune signaling; experimental, not an approved drug.

statusbioassayed targetVPAC1 length28 aa refs2
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 5 / 5
prediction metrics boltz-2 2.2.1
ipTM0.890
pTM0.872
avg pLDDT50.2
ranking score0.580
STRUCTURE · PEP-10469 × VPAC1
ranking0.580
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 2.2.1 · mmCIF ↓ download
sequence28 aa
151015202528
HSDAVFTDNYTRLR KQLAVKKYLNSILN
Hypotheses5 directions▾ collapse

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.

openupdated 2026-06-05

Does this peptide preferentially activate the PAC1 receptor rather than the VPAC2 receptor that causes dangerous vasodilation?

If true, this peptide could open a path to treating neurological conditions and inflammatory diseases where VIP-like signals are beneficial, without the cardiovascular toxicity that has blocked VIP from clinical use. Patients with conditions like Parkinson's disease or inflammatory bowel disease could potentially benefit.

The hypothesis
Pep-10469 is a dual PAC1/VPAC1 partial agonist rather than a selective VIP receptor ligand, because its 28-amino-acid sequence (HSDAVFTDNYTRLRKQLAVKKYLNSILN) shares the N-terminal His-Ser-Asp-Ala-Val-Phe-Thr motif conserved across VIP, PACAP-27, and glucagon-family peptides that is required for class B GPCR activation, while its C-terminal divergence from canonical VIP (position 17 onward: KQLAVKKYLNSILN vs. KQYLAAVQKYLNSILN) would reduce VPAC2 affinity.
Why it’s plausible
Class B GPCRs, including PAC1 and VPAC1, are activated by the N-terminal region of peptide ligands, with receptor selectivity encoded in the C-terminal helix. The N-terminal HSDAVFT of pep-10469 is identical to VIP residues 1-7 and nearly identical to PACAP residues 1-7 (HSDGIFT). The C-terminal divergence from VIP at positions 17-28 would alter the helical amphipathicity that drives VPAC2 selectivity. Bourgault et al. demonstrated that systematic modification of the PACAP C-terminus shifts PAC1 vs. VPAC selectivity (10.1111/j.1476-5381.2011.01676.x). The His1 retention predicts agonist rather than antagonist behavior, consistent with HDX data showing N-terminal peptides stabilize class B receptor extracellular domains (10.1038/ncomms8859).
Why it matters
If pep-10469 activates PAC1 preferentially over VPAC2, it could dissociate neuroprotective PAC1-mediated signaling from the vasodilatory VPAC2-mediated side effects that make native VIP clinically toxic even at submicrogram doses, addressing a longstanding pharmacological bottleneck for VIP-axis therapeutics.
Plausibility.75
Novelty.50
Impact.70
Basis · grounding3 papers · 1 computed/note
[1]
sequenceN-terminal HSDAVFT matches VIP residues 1-7 exactly; His1 intact, predicting agonism not antagonism
[2]
paper
Bourgault et al. show C-terminal modifications of PACAP/VIP analogs selectively tune PAC1 vs. VPAC receptor affinity
doi: 10.1111/j.1476-5381.2011.01676.x
[3]
paper
VIP produces toxic vasodilatory effects even at submicrogram doses, motivating selective receptor targeting
doi: 10.7150/thno.4024
[4]
paper
VIP/VPAC receptor structure-function work establishes that C-terminal helix governs subtype selectivity
doi: 10.1021/ml400257h
openupdated 2026-06-05

Could this peptide help the pancreas release insulin through a receptor that current diabetes medications do not target?

If this peptide works through a different channel than GLP-1 drugs like semaglutide, it could potentially be combined with those drugs to help the many patients with type 2 diabetes who still have poorly controlled blood sugar on existing treatments. This could matter for millions of people worldwide.

The hypothesis
Pep-10469, through PAC1 receptor agonism in pancreatic islets, could potentiate glucose-stimulated insulin secretion in a manner that is mechanistically distinct from GLP-1 receptor agonists, because PAC1 and GLP-1R signal through overlapping but non-identical cAMP and PKA pathways in beta cells, predicting additive rather than redundant insulinotropic effects when combined with existing GLP-1-based therapies.
Why it’s plausible
PAC1 is expressed in pancreatic beta cells, where PACAP and VIP promote glucose-stimulated insulin secretion via cAMP elevation. The N-terminal HSDAVFT motif of pep-10469 is structurally analogous to glucagon-family peptide activators of class B GPCRs (10.1038/ncomms8859). GLP-1R agonists are the dominant class of diabetes drugs, but patient response is heterogeneous, partly because PAC1 and GLP-1R drive distinct downstream effectors in beta cells. A PAC1-selective agonist would not compete with GLP-1R for receptor occupancy, potentially enabling combination regimens with additive glycemic control. The precedent of VIP/PACAP effects on islet function (10.2337/diabetes.51.5.1453) grounds this application.
Why it matters
If pep-10469 acts as an adjunct to GLP-1R agonists in type 2 diabetes through a non-overlapping receptor mechanism, it could provide incremental glycemic benefit for patients who respond partially to current therapies, a substantial unmet need given the prevalence of residual hyperglycemia on existing treatments.
Plausibility.55
Novelty.50
Impact.60
Basis · grounding3 papers · 1 computed/note
[1]
sequenceN-terminal HSDAVFT is structurally homologous to glucagon-family class B GPCR activators; His1 predicts agonism at PAC1 expressed in pancreatic islets
[2]
paper
VPAC1/PACAP receptor pharmacology in metabolic contexts; VIP-family peptides modulate islet function
doi: 10.2337/diabetes.51.5.1453
[3]
paper
Glucagon-family peptide binding to class B GPCRs stabilizes receptor in active conformations relevant to insulin secretion signaling
doi: 10.1038/ncomms8859
[4]
paper
VIP and VIP receptor biology review discusses pancreatic and metabolic roles of VIP-family signaling
doi: 10.1021/ml400257h
openupdated 2026-06-05

Does this peptide have weaker effects on immune cells than native VIP, while still protecting nerve cells?

If true, this peptide could be used to treat neurological diseases in patients who cannot afford to have their immune system weakened, including elderly patients or those on other immune-suppressing medications. This could expand who is eligible for this type of treatment.

The hypothesis
The substitution of canonical VIP residue Tyr10 with Asn10 (position 10 in pep-10469 is Asn: ...DNYTRL..., giving Tyr at position 11 not 10) and the altered spacing of hydrophobic residues in the C-terminal segment reduce VPAC1-mediated immunosuppression relative to native VIP, potentially preserving anti-inflammatory selectivity at PAC1-expressing neurons without broadly dampening immune surveillance.
Why it’s plausible
Native VIP is a potent immunosuppressant acting primarily through VPAC1 on immune cells, which limits its therapeutic use in infection-prone patients. The C-terminal sequence of pep-10469 (KQLAVKKYLNSILN) differs from VIP (KQYLAAVQKYLNSILN) at multiple positions that prior mutagenesis studies have shown to be critical for VPAC1 affinity. Selective attenuation of VPAC1 signaling in immune cells while retaining PAC1 activity in neurons would allow neuroprotective use without immunosuppression, which is a reported limitation of VIP-based therapies.
Why it matters
Dissociating neuroprotection from immunosuppression in a VIP-family peptide would represent a meaningful advance for potential use in neurodegenerative diseases where patients are already immunocompromised or infection-susceptible.
Plausibility.50
Novelty.50
Impact.60
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal sequence KQLAVKKYLNSILN diverges from VIP at positions 17-28, altering residues shown by mutagenesis to affect VPAC1 selectivity
[2]
paper
Work on high-affinity selective VPAC1 antagonists establishes which structural features distinguish VPAC1 from PAC1 selectivity
doi: 10.2337/diabetes.51.5.1453
[3]
paper
VIP receptor structure-function review details residue-level determinants of receptor subtype selectivity
doi: 10.1021/ml400257h
openupdated 2026-06-05

Does this peptide form the right folded shape to activate its receptor while avoiding the membrane damage that makes similar peptides toxic?

If the peptide can activate its target receptor without disrupting cell membranes, it could be used at higher doses or for longer durations than native VIP, potentially making it effective for chronic conditions like neurodegeneration or chronic inflammatory disease where sustained treatment is needed.

The hypothesis
The C-terminal YLNSILN segment of pep-10469 adopts a stable amphipathic alpha-helix in a membrane-mimetic environment, and this helix is shorter and less hydrophobic than the equivalent VIP segment, predicting reduced membrane-disruptive activity but preserved helical receptor-contact geometry at the class B GPCR extracellular domain.
Why it’s plausible
Class B GPCR peptide ligands typically adopt a helical conformation upon receptor binding, with the helix forming key contacts with the extracellular domain. The C-terminal YLNSILN of pep-10469 contains Leu, Ile, and Leu as hydrophobic residues on one face, with Asn and Ser on the polar face, consistent with a moderate-stability amphipathic helix. Compared to VIP's C-terminus (AVQKYLNSILN), the pep-10469 variant lacks the extended hydrophobic stretch that in native VIP promotes both receptor binding and non-specific membrane insertion. This structural distinction could explain both reduced receptor affinity and, importantly, reduced membrane lytic activity that can cause toxicity at high concentrations.
Why it matters
A VIP analog with preserved helical receptor-contact geometry but reduced membrane insertion propensity would have a wider therapeutic window, directly addressing the dose-limiting toxicity described for VIP-class peptides.
Plausibility.55
Novelty.45
Impact.55
Basis · grounding3 papers · 1 computed/note
[1]
sequenceYLNSILN contains Leu-Ile-Leu hydrophobic face and Asn-Ser polar face consistent with amphipathic helix; absent the extended hydrophobic run of native VIP C-terminus
[2]
paper
HDX data for glucagon-family peptide-GCGR complexes shows C-terminal helix stabilizes extracellular stalk region of class B GPCRs
doi: 10.1038/ncomms8859
[3]
paper
VIP toxicity is dose-limiting and may partly reflect membrane perturbation at higher concentrations
doi: 10.7150/thno.4024
[4]
paper
Bourgault et al. correlate C-terminal helical stability of PACAP analogs with receptor potency and selectivity
doi: 10.1111/j.1476-5381.2011.01676.x
openupdated 2026-06-05

Do the positively charged parts of this peptide stick to sugar-coated proteins on brain cell surfaces, concentrating it near where it needs to work?

If the peptide naturally accumulates at the right cell surfaces, it could work at lower doses than expected, reducing the risk of side effects. This would matter most for neurological treatments where getting enough drug to the brain while limiting body-wide exposure is a key challenge.

The hypothesis
The Lys20-Lys21 di-lysine motif in pep-10469 (KQLAVKK, positions 19-25 of the sequence) confers heparan sulfate proteoglycan binding that extends receptor residence time at neuronal synaptic membranes, analogously to the mechanism described for other cationic neuropeptides, independent of its GPCR pharmacology.
Why it’s plausible
The sequence HSDAVFTDNYTRLRKQLAVKKYLNSILN contains a cluster of positively charged residues: Arg14, Lys15, Lys20, Lys21. This XBBXBX-like motif (where B is a basic residue) is a recognized heparan sulfate binding signature. Heparan sulfate proteoglycans on neuronal surfaces act as co-receptors that concentrate peptide ligands near their cognate GPCRs, prolonging effective local concentration and slowing diffusion away from the synapse. This mechanism would be distinct from, and additive with, direct GPCR binding, meaning the peptide's in vivo potency could exceed predictions from receptor binding assays alone.
Why it matters
If heparan sulfate binding concentrates pep-10469 at synaptic membranes, its effective receptor-level potency in vivo would be substantially higher than in vitro binding assays suggest, which has direct implications for dosing predictions and for avoiding the off-target toxicity associated with systemic VIP administration.
Plausibility.45
Novelty.55
Impact.50
Basis · grounding2 papers · 1 computed/note
[1]
sequenceArg14, Lys15, Lys20, Lys21 form a cationic cluster consistent with heparan sulfate proteoglycan binding motifs (XBBXBX pattern)
[2]
paper
VIP's toxicity at submicrogram doses implies very high potency that may partly reflect in vivo concentrating mechanisms not captured in isolated receptor assays
doi: 10.7150/thno.4024
[3]
paper
VIP receptor biology review discusses how peptide charge and amphipathicity influence receptor engagement in membrane contexts
doi: 10.1021/ml400257h
details expand to inspect
full evidence table1 metrics
metricvaluetool
IC50 0.11 nM GPCRDB/ChEMBL
3-letter notation
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Leu-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
recipeboltz-2 2.2.1
parametervalue
modelboltz-2 2.2.1
weights
hardwarevast_v100_32gb
mlx version
python
random seed1
msa strategycolabfold_local
runtime
predicted by
predicted at2026-05-22
citationbibtex
peptidemodel (2026). Experimental peptide targeting a VIP receptor (CHEMBL3884667) (pep-10469, v1). PeptideModel. https://peptidemodel.com/card/pep-10469
@peptide{pep10469,
  sequence = {HSDAVFTDNYTRLRKQLAVKKYLNSILN},
  target   = {vpac1},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
clinical trials 0 trials · checked 2026-05-22
0
no registered clinical trials as of 2026-05-22; we'll re-check periodically
references 2 papers
discussion no comments
sign in to comment
peptidemodel.com CC-BY-SA-4.0 research only · not for human use