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ID: ALA4699634
Journal: J Med Chem
Title: Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.
Authors: Alleyne C,Amin RP,Bhatt B,Bianchi E,Blain JC,Boyer N,Branca D,Embrey MW,Ha SN,Jette K,Johns DG,Kerekes AD,Koeplinger KA,LaPlaca D,Li N,Murphy B,Orth P,Ricardo A,Salowe S,Seyb K,Shahripour A,Stringer JR,Sun Y,Tracy R,Wu C,Xiong Y,Youm H,Zokian HJ,Tucker TJ
Abstract: Proprotein 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.
CiteXplore: 33170686