2. Academic Validation
  3. Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2

Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2

  • Cell Chem Biol. 2021 Jun 17;28(6):855-865.e9. doi: 10.1016/j.chembiol.2021.04.020.
Hengyue Shan 1,  Jianping Liu 2,  Jiali Shen 1,  Jialin Dai 3,  Gang Xu 4,  Kuankuan Lu 1,  Chao Han 1,  Yaru Wang 5,  Xiaolong Xu 5,  Yilun Tong 1,  Huaijiang Xiang 3,  Zhiyuan Ai 3,  Guanglei Zhuang 6,  Junhao Hu 3,  Zheng Zhang 7,  Ying Li 8,  Lifeng Pan 9,  Li Tan 10
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 4 Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China.
  • 5 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.
  • 6 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 7 Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China. Electronic address: zhangzheng1975@aliyun.com.
  • 8 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. Electronic address: liying@sioc.ac.cn.
  • 9 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. Electronic address: panlf@sioc.ac.cn.
  • 10 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. Electronic address: tanli@sioc.ac.cn.
PMID: 33979649 DOI: 10.1016/j.chembiol.2021.04.020
Abstract

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.

Keywords

COVID-19; SARS-CoV-2; assay development; high-throughput screening; lead optimization; papain-like protease; small-molecule inhibitor; structure-based design.

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