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
  • 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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