Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design

In the last few years macrocyclic peptides have emerged as a better class of lead candidates for inhibition of protein-protein interactions with respect to conventional small molecules. The IRBM peptide chemistry team collaborated with the teams at Merck & co. and RaPharma to develop potent macrocyclic peptide inhibitors of PCSK9 a key regulator of plasma LDL-cholesterol.

The work just published in the Journal of Medicinal Chemistry, describes the generation of novel bicyclic PCSK9 peptide inhibitors. Starting from a macrocyclic peptide lead selected by in vitro mRNA display technologies and using a structure-based drug design approach, the team was able to optimize the potency and metabolic stability while minimizing the MW.  This new series of peptide inhibitors serve as new leads for the development of potential oral, once daily therapeutics for the treatment of cardiovascular diseases.