Cell Chemical Biology p. 855 - 9,865 (2021)
Update date:2022-08-02
Topics:
Shan, Hengyue
Liu, Jianping
Shen, Jiali
Dai, Jialin
Xu, Gang
Lu, Kuankuan
Han, Chao
Wang, Yaru
Xu, Xiaolong
Tong, Yilun
Xiang, Huaijiang
Ai, Zhiyuan
Zhuang, Guanglei
Hu, Junhao
Zhang, Zheng
Li, Ying
Pan, Lifeng
Tan, Li
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 IC50. 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.
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