From mRNA Lead to Drug Candidate-Discovery of a Novel, Potent, and Orally Bioavailable, Tricyclic Peptide PCSK9 Inhibitor
Chengwei Wu
Senior Scientist, Merck Research Laboratories
This talk highlighted the discovery of a tricyclic peptide PCSK9 inhibitor having similar pharmacodynamic effects in cynomolgus monkeys to the FDA-approved, parenterally dosed antiPCSK9 mAb, with the advantage of oral administration. From the original cyclic peptide hit generated from mRNA display screening, we applied a structure-guided design through stabilization and rigidification of the peptide to improve binding potency and metabolic stability. Simultaneously, we engineered out several unfavorable off-target issues through charge modification of a key sidechain using newly derived SAR. Finally, we demonstrated that with an enabled formulation, oral dosed optimized molecules had sufficient oral bioavailability to maintain therapeutical levels in rats and primates.
Chengwei Wu is a Senior Scientist at Merck Research Laboratories in West Point, PA. She has broad expertise in drug discovery across modalities, specializing in peptide and protein chemistry design and synthesis. She has been a productive contributor to many discovery programs across Vaccine Research and Discovery Chemistry. More recently, she was a key member of the cross-site oral PCSK9 discovery team responsible for hit expansion and optimization of a cyclic peptide hit from mRNA display to candidate selection.