Fatty-acid tags extend a CGRP peptide's life, but at a cost to potency
- A 10-residue CGRP receptor antagonist peptide was decorated with lipid groups of differing chain length and PEG linkers, plus N-terminal changes, to build a migraine lead.
- A C18 diacid lipid gave the longest mouse half-life, and serum stability rose with lipid size, but receptor antagonism weakened.
- A fast, low-cost, HPLC-based assay for peptide binding to human serum albumin was also introduced, avoiding the membrane-adsorption and degradation problems of equilibrium dialysis.
💡 Points Based on the abstract
Potency loss with bigger lipids smells like the tag is crowding the receptor's extracellular domain, where small peptide antagonists bind. Semaglutide-style C18 diacid with a spacer is the obvious benchmark, so I'd want the potency-versus-albumin-binding trade-off plotted per analog. Also check whether serum-shifted potency, not buffer potency, still supports the dosing.
Lipid-Modified CGRP Receptor Antagonists: Balancing Pharmacokinetic Improvement and Potency Loss ↗