Key result
Multi-receptor antagonists linking CGRP8-37 and PACAP6-38 successfully blocked both CGRP and PACAP activity in vitro, with one variant showing greater potency than the parental CGRP antagonist.
Why the study?
Simultaneously blocking both CGRP and PACAP signaling could provide clinical advantage over individual blockade, but proof-of-concept for generating covalently linked multi-receptor peptide antagonists was needed.
Answers are grounded in this paper and cite their sources.
This proof-of-concept study demonstrates that multi-receptor antagonists can be successfully generated to simultaneously block CGRP and PACAP activity, offering a potential novel therapeutic strategy for migraine and pain.
Objective This study aimed to provide proof‐of‐concept that multi‐receptor antagonist peptides can be generated by covalently linking independent antagonist peptides that block calcitonin gene‐related peptide (CGRP 8‐37 ) or pituitary adenylate cyclase‐activating peptide (PACAP)/vasoactive intestinal peptide (VIP) (PACAP 6‐38 ) activity. Background The neuropeptides CGRP and PACAP are implicated in migraine and pain pathogenesis. CGRP and PACAP are elevated during a migraine attack, and following infusion of either peptide, patients develop migraine‐like attacks. This indicates that targeting both these systems may provide therapeutic benefits. Mechanistic studies suggest that these peptides largely act independently from one another. Therefore, blocking the activity of both CGRP and PACAP simultaneously could provide a clinical advantage over individual blockade. One strategy is to develop a single antagonist capable of inhibiting the signaling of both CGRP and PACAP receptors, a multi‐receptor antagonist. N‐terminal truncation of CGRP and PACAP generates the antagonists CGRP 8‐37 and PACAP 6‐38 , respectively. These are commonly used as research tools for the CGRP and PACAP receptors. These peptide antagonists were, therefore, used as the basis for the design of multi‐receptor antagonists against the CGRP and PACAP receptors and to test their functionality in vitro. Methods To generate multi‐receptor antagonists, CGRP 8‐37 was linked through 1,3‐dipolar cycloaddition using click chemistry to PACAP 6‐38 at amino acid residues 21, 34, or 38. The ability of these multi‐receptor antagonists to block CGRP activity (CGRP and AMY 1 receptors) and PACAP‐38, PACAP‐27, and VIP activity (PAC 1 , VPAC 1 , and VPAC 2 receptors) was then characterized in transfected Cos7 cells. The peptides were then further examined in pain‐relevant rat spinal cord cultures, as a model of endogenous receptors. Results Multi‐receptor antagonists were successfully generated, displaying similar antagonist potency to their parental antagonists in both transfected Cos7 cells and in spinal cord cultures. Interestingly, CGRP 8‐37 linked to position 38 of PACAP 6‐38 was a more potent antagonist of CGRP activity than CGRP 8‐37 . Conclusion This study provides proof‐of‐concept evidence for the development of potent multi‐receptor antagonists capable of blocking both CGRP and PACAP activity.
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Tasma et al. (2025) studied Migraine and pain pathogenesis. Multi-receptor antagonist peptides (CGRP8-37 linked to PACAP6-38) vs. Parental antagonists (CGRP8-37 and PACAP6-38) was evaluated on Antagonist potency in transfected Cos7 cells and rat spinal cord cultures. Multi-receptor antagonists linking CGRP8-37 and PACAP6-38 successfully blocked both CGRP and PACAP activity in vitro, with one variant showing greater potency than the parental CGRP antagonist.
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