An affinity-based screen of 10<sup>13</sup> macrocyclic peptides identified PCSK9 ligands with high affinity and partial disruption of LDLR binding. The structure of the peptides in complex with PCSK9 revealed a novel, induced-fit pocket, as well as insights into key binding contacts and opportunities to enhance disruptor function. Structure-based design led to macrocyclic peptides with enhanced function, pharmacokinetic properties, and pharmacologic inhibition of PCSK9 in mice.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.