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.
J Med Chem. 2020 Nov 25;63(22):13796-13824. doi: 10.1021/acs.jmedchem.0c01084. Epub 2020 Nov 10.
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 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as . 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.
前蛋白转化酶枯草溶菌素 9（PCSK9）是血浆 LDL-胆固醇（LDL-C）的关键调节剂，也是治疗高胆固醇血症和冠状动脉疾病的临床验证靶点。在本文中，我们描述了一系列新型环状肽，这些环状肽来源于 mRNA 展示筛选，可抑制 PCSK9 和 LDLR 之间的蛋白-蛋白相互作用。通过基于结构的药物设计方法，我们能够对原始筛选先导物进行修饰，以优化其效力、代谢稳定性，并最小化分子量，从而提供新型双环下一代 PCSK9 抑制剂肽，如 。这些下一代肽为进一步探索潜在的口服、每日一次的 PCSK9 治疗心血管疾病的疗法提供了重要基础。
