Computational Design, Synthesis, and Evaluation of Stapled Peptide-Based Antagonists of the CGRP Receptor

Hydrocarbon-stapled peptide antagonists targeting the
calcitonin
gene-related peptide (CGRP) receptor represent a promising strategy
for migraine therapy. This study uses computational design tools and
molecular dynamics simulations to develop novel stapled peptide antagonists
conferring improved potency and stability compared to CGRP(8–37)-NH2. Peptides with varied staple geometries and unnatural amino
acids were assessed using circular dichroism and antagonism and serum
stability assays. A stapled peptide (4), containing an
S5/S5 i,i+4 hydrocarbon staple at
positions 12 and 16, exhibited enhanced serum stability (compared
to CGRP(8–37)-NH2) and retained antagonist activity.
Notably, Aib36-containing peptides (16–19) remained intact following prolonged serum stability exposure, but
lost receptor antagonism. While the computational predictions of helicity
and receptor binding largely corresponded to experimental outcomes,
this trend was inconsistent, highlighting current in silico limitations. Moreover, this work advances the understanding of peptide
structure–stability–activity trade-offs and informs
future peptide therapeutic development, with particular implications
for overcoming metabolic instability in peptide-based drugs.