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

被引：64

作者：

Shan, Hengyue ^{[1
,2
]}

Liu, Jianping ^{[3
]}

Shen, Jiali ^{[1
,2
]}

Dai, Jialin ^{[1
]}

Xu, Gang ^{[4
]}

Lu, Kuankuan ^{[1
,2
]}

Han, Chao ^{[1
,2
]}

Wang, Yaru ^{[2
,3
]}

Xu, Xiaolong ^{[2
,3
]}

Tong, Yilun ^{[1
,2
]}

Xiang, Huaijiang ^{[1
]}

Ai, Zhiyuan ^{[1
]}

Zhuang, Guanglei ^{[5
]}

Hu, Junhao ^{[1
]}

Zhang, Zheng ^{[4
]}

Li, Ying ^{[1
]}

Pan, Lifeng ^{[2
,3
]}

Tan, Li ^{[1
]}

机构：

[1] Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, Shanghai 201210, Peoples R China

[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China

[4] Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Natl Clin Res Ctr Infect Dis,Inst Hepatol,Sch Med, Shenzhen 518112, Guangdong, Peoples R China

[5] Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Shanghai Canc Inst,State Key Lab Oncogenes & Rela, Shanghai 200240, Peoples R China

来源：

CELL CHEMICAL BIOLOGY | 2021年 / 28卷 / 06期

基金：

中国国家自然科学基金;

关键词：

SMALL-MOLECULE INHIBITOR; IN-VITRO; UBIQUITIN; APOPTOSIS; RECOGNITION; DISCOVERY; GROWTH; MODEL;

D O I：

10.1016/j.chembiol.2021.04.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：855 / +

页数：20

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