Douglas G Johns, Louis-Charles Campeau, Puja Banka, An Bautmans, Tjerk Bueters, Elisabetta Bianchi, Danila Branca, Paul G Bulger, Inne Crevecoeur, Fa-Xiang Ding, Robert M Garbaccio, Erik D Guetschow, Yan Guo, Sookhee N Ha, Jennifer M Johnston, Hubert Josien, Eunkyung A Kauh, Kenneth A Koeplinger, Jeffrey T Kuethe, Eseng Lai, Christine L Lanning, Anita Y H Lee, Li Li, Anilkumar G Nair, Edward A O'Neill, S Aubrey Stoch, David A Thaisrivongs, Thomas J Tucker, Petr Vachal, Kristien van Dyck, Frederic P Vanhoutte, Bram Volckaert, Dennis G Wolford, Andy Xu, Tian Zhao, Dan Zhou, Susan Zhou, Xiaohong Zhu, Hratch J Zokian, Abbas M Walji, Harold B Wood
BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9...
July 11, 2023: Circulation