jm0c01084_si_005.pdb (275.96 kB)
Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design
dataset
posted on 2020-11-10, 18:15 authored by Candice Alleyne, Rupesh P. Amin, Bhavana Bhatt, Elisabetta Bianchi, J. Craig Blain, Nicolas Boyer, Danila Branca, Mark W. Embrey, Sookhee N. Ha, Kelli Jette, Douglas G. Johns, Angela D. Kerekes, Kenneth A. Koeplinger, Derek LaPlaca, Nianyu Li, Beth Murphy, Peter Orth, Alonso Ricardo, Scott Salowe, Kathleen Seyb, Aurash Shahripour, Joseph R. Stringer, Yili Sun, Rodger Tracy, Chengwei Wu, Yusheng Xiong, Hyewon Youm, Hratch J. Zokian, Thomas J. TuckerProprotein convertase subtilisin-like/kexin
type 9 (PCSK9) is a
key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated
target for the treatment of hypercholesterolemia and coronary artery
disease. In this paper, we describe a series of novel cyclic peptides
derived from an mRNA display screen which inhibit the protein–protein
interaction between PCSK9 and LDLR. Using a structure-based drug design
approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize
the molecular weight to provide novel bicyclic next-generation PCSK9
inhibitor peptides such as 78. These next-generation
peptides serve as a critical foundation for continued exploration
of potential oral, once-a-day PCSK9 therapeutics for the treatment
of cardiovascular disease.
