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

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

  • J Med Chem. 2020 Nov 25;63(22):13796-13824. doi: 10.1021/acs.jmedchem.0c01084.
Candice Alleyne 1,  Rupesh P Amin 2,  Bhavana Bhatt 2,  Elisabetta Bianchi 3,  J Craig Blain 4,  Nicolas Boyer 4,  Danila Branca 3,  Mark W Embrey 5,  Sookhee N Ha 6,  Kelli Jette 4,  Douglas G Johns 7,  Angela D Kerekes 8,  Kenneth A Koeplinger 9,  Derek LaPlaca 4,  Nianyu Li 2,  Beth Murphy 7,  Peter Orth 10,  Alonso Ricardo 4,  Scott Salowe 7,  Kathleen Seyb 4,  Aurash Shahripour 8,  Joseph R Stringer 4,  Yili Sun 4,  Rodger Tracy 9,  Chengwei Wu 5,  Yusheng Xiong 8,  Hyewon Youm 8,  Hratch J Zokian 7,  Thomas J Tucker 5
Affiliations

Affiliations

  • 1 Discovery Pharmaceutical Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 2 Safety Assessment, Merck & Comapny, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 3 IRBM S.p.A., Via Pontina km 30600, Pomezia, Rome 00071, Italy.
  • 4 UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
  • 5 Departments of Medicinal Chemistry, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 6 Modeling and Informatics, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 7 Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 8 Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 9 Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 10 Structural Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 33170686 DOI: 10.1021/acs.jmedchem.0c01084
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.

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