Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Cell Chem Biol. 2021 Jun 17;28(6):855-865.e9. doi: 10.1016/j.chembiol.2021.04.020. Epub 2021 Apr 27.
The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.
新型冠状病毒肺炎疫情给社会带来了灾难性的影响，我们急需有效的药物。SARS-CoV-2（SCoV2）的木瓜蛋白酶样蛋白酶结构域（PLpro）对于病毒复制是不可或缺的，是潜在的药物干预靶点。在这项工作中，我们描述了一种强效和选择性的 SCoV2 PLpro 抑制剂 19 的开发。该抑制剂不仅能有效阻断 PLpro 介导的底物切割和免疫抑制功能，而且能显著抑制人细胞中的 SCoV2 复制，IC50 低至亚微摩尔。我们进一步提供了一种方便、灵敏的活性探针 7，以及互补的测定方法，可用于在体外或细胞内快速评估 SCoV2 PLpro 抑制剂。此外，我们还揭示了 SCoV2 PLpro 与原型抑制剂复合物的共晶结构，阐明了它们的详细结合模式。总之，这些发现为针对 SCoV2 PLpro 的药物发现提供了有前景的先导化合物和重要的工具。
