Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Department of Biochemistry, College of Natural and Agricultural Sciences, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
J Med Chem. 2021 Apr 22;64(8):4903-4912. doi: 10.1021/acs.jmedchem.1c00005. Epub 2021 Apr 2.
Modulating disease-relevant protein-protein interactions (PPIs) using pharmacological tools is a critical step toward the design of novel therapeutic strategies. Over the years, however, targeting PPIs has proven a very challenging task owing to the large interfacial areas. Our recent efforts identified possible novel routes for the design of potent and selective inhibitors of PPIs using a structure-based design of covalent inhibitors targeting Lys residues. In this present study, we report on the design, synthesis, and characterizations of the first Lys-covalent BH3 peptide that has a remarkable affinity and selectivity for hMcl-1 over the closely related hBfl-1 protein. Our structural studies, aided by X-ray crystallography, provide atomic-level details of the inhibitor interactions that can be used to further translate these discoveries into novel generation, Lys-covalent pro-apoptotic agents.
利用药理学工具调节与疾病相关的蛋白质-蛋白质相互作用（PPIs）是设计新型治疗策略的关键步骤。然而，多年来，由于界面面积大，靶向 PPIs 被证明是一项极具挑战性的任务。我们最近的努力确定了使用针对赖氨酸残基的共价抑制剂的基于结构的设计来设计有效且选择性的 PPI 抑制剂的可能新途径。在本研究中，我们报告了第一个 Lys-共价 BH3 肽的设计、合成和表征，该肽对 hMcl-1 具有显著的亲和力和选择性，而对密切相关的 hBfl-1 蛋白则没有。我们的结构研究得到了 X 射线晶体学的帮助，提供了抑制剂相互作用的原子水平细节，可用于将这些发现进一步转化为新型 Lys-共价促凋亡剂。
