Lipid-Modified CGRP Receptor Antagonists: Balancing Pharmacokinetic Improvement and Potency Loss

Abstract Lipidation is a promising strategy for enhancing peptide stability by reducing proteolytic degradation and prolonging systemic exposure. In this study, we systematically evaluated lipid motifs varying in lipid chain length and PEG spacer composition, combined with peptide N-terminal modifications, using a 10-mer calcitonin gene-related peptide receptor antagonist to optimize a candidate for migraine treatment. Incorporation of a C18 diacid lipid motif increased the in vivo (mouse) half-life to 3.5 h. Although lipidation improved serum stability in a size-dependent manner, it was accompanied by a reduction in receptor antagonism, highlighting the balance between pharmacokinetic enhancement and biological activity. These findings improve our understanding of the trade-offs involved in lipidated peptide design and support future optimization strategies. In addition, we developed a rapid, inexpensive, and HPLC-compatible assay for quantifying peptide binding to human serum albumin, overcoming limitations of conventional equilibrium dialysis methods, including non-specific membrane binding, lengthy equilibration times, and peptide degradation.