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

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Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-10 , 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

Affiliation

Discovery Pharmaceutical Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Safety Assessment, Merck & Comapny, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States
IRBM S.p.A., Via Pontina km 30600, Pomezia, Rome 00071, Italy
UCB Ra Pharma, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States
Departments of Medicinal Chemistry, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States
Modeling and Informatics, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Discovery Biology, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Departments of Medicinal Chemistry, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Company, Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States
Structural Sciences, Merck & Company, Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States

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.

中文翻译：

从mRNA显示屏衍生并通过基于结构的设计优化的一系列新型和高效环肽PCSK9抑制剂

前蛋白转化酶类枯草杆菌蛋白酶样/ kexin型9（PCSK9）是血浆LDL-胆固醇（LDL-C）的关键调节剂，并且是经临床验证的高胆固醇血症和冠状动脉疾病的治疗靶标。在本文中，我们描述了一系列源自mRNA显示屏的新型环肽，这些环肽可抑制PCSK9与LDLR之间的蛋白质相互作用。使用基于结构的药物设计方法，我们能够修改原始的筛选前导2，以优化药效和代谢稳定性并最小化分子量，从而提供新型的双环新一代PCSK9抑制剂肽，例如78。这些下一代肽为继续探索潜在的口服每日一次PCSK9治疗心血管疾病的关键基础。

更新日期：2020-11-25

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