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

Autor:	Alleyne C; Discovery Pharmaceutical Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Amin RP; Safety Assessment, Merck & Comapny, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Bhatt B; Safety Assessment, Merck & Comapny, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Bianchi E; IRBM S.p.A., Via Pontina km 30600, Pomezia, Rome 00071, Italy., Blain JC; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Boyer N; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Branca D; IRBM S.p.A., Via Pontina km 30600, Pomezia, Rome 00071, Italy., Embrey MW; Departments of Medicinal Chemistry, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Ha SN; Modeling and Informatics, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Jette K; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Johns DG; Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Kerekes AD; Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Koeplinger KA; Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., LaPlaca D; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Li N; Safety Assessment, Merck & Comapny, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Murphy B; Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Orth P; Structural Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Ricardo A; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Salowe S; Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Seyb K; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Shahripour A; Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Stringer JR; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Sun Y; UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Tracy R; Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Wu C; Departments of Medicinal Chemistry, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Xiong Y; Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Youm H; Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Zokian HJ; Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Tucker TJ; Departments of Medicinal Chemistry, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Nov 25; Vol. 63 (22), pp. 13796-13824. Date of Electronic Publication: 2020 Nov 10.
DOI:	10.1021/acs.jmedchem.0c01084
Abstrakt:	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.
Databáze:	MEDLINE
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