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Study breakdown

First multi-receptor antagonist peptide simultaneously blocks both CGRP and PACAP migraine pathways

RPEP-137782025Tasma, Zoe; Siow, Andrew; Harris, Paul W R; Brimble, Margaret A; Hay, Debbie L; Walker, Christopher S
evidence
The takeaway

Click chemistry-linked CGRP8-37 and PACAP6-38 antagonists created novel dual-receptor blockers with preserved potency against both CGRP and PACAP receptors in transfected cells and pain-relevant spinal cord cultures.

Dual blockade in one molecule

First multi-receptor peptide antagonist simultaneously blocks 5 CGRP and PACAP receptors—potentially superior to single-target migraine drugs

What the researchers found

Three multi-receptor antagonists created by click chemistry. Maintained potency vs parental antagonists at all receptors (CGRP-R, AMY1, PAC1, VPAC1, VPAC2). Position 38 linkage: enhanced CGRP antagonism. Validated in Cos7 cells AND spinal cord cultures (endogenous receptors).

Why it matters

Both CGRP and PACAP drive migraine, but current drugs target only one. A single molecule blocking both could provide superior migraine prevention for patients who do not fully respond to CGRP-only therapy.

How the study worked

Click chemistry (1,3-dipolar cycloaddition) linking CGRP8-37 to PACAP6-38 at positions 21, 34, or 38. cAMP accumulation assays in Cos7 cells. Pain-relevant rat spinal cord cultures.

What this study cannot tell us

In vitro proof of concept. Peptide antagonists have poor in vivo pharmacokinetics. No animal migraine model testing. Click chemistry linkage may affect in vivo stability.

How to read the evidence

In vitro proof of concept with two validation systems. Novel drug design approach needing in vivo testing.

When this study was published

Published in 2025.

The bigger picture

Multi-receptor antagonist peptides represent a new drug design paradigm. Rather than combining two drugs, a single molecule addresses two disease pathways—potentially reducing costs and complexity.

Questions still open

  • Could these multi-antagonists be tested in animal migraine models?
  • Would formulation (PEGylation, nanoparticle) improve in vivo pharmacokinetics?
  • Is dual CGRP+PACAP blockade superior to single blockade in clinical migraine?

Common questions

Why block both CGRP and PACAP for migraine?
Both neuropeptides independently trigger migraine attacks and are elevated during attacks. Current drugs block only CGRP. Patients who do not fully respond to CGRP therapy may benefit from simultaneous PACAP blockade. This study created the first single molecule that blocks both pathways.
How was this dual-blocking peptide made?
The researchers used click chemistry to covalently link two existing peptide antagonists—one blocking CGRP and one blocking PACAP—into a single molecule. The combined peptide maintained the blocking ability of both parent molecules and even showed enhanced CGRP potency at one linkage position.

Read the original research

Development and pharmacological characterization of novel multi- calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide receptor antagonists.

Headache, 65(7), 1064-1079

View on PubMed ↗Publisher’s paper ↗

Citation

Tasma, Zoe; Siow, Andrew; Harris, Paul W R; Brimble, Margaret A; Hay, Debbie L; Walker, Christopher S. (2025). Development and pharmacological characterization of novel multi- calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide receptor antagonists.. Headache, 65(7), 1064-1079. https://doi.org/10.1111/head.14916