Characterization and noncovalent inhibition of the K63-deubiquitinase activity of SARS-cov-2 PLpro

被引：0

作者：

Liu, Xin ^{[1
]}

Zheng, Miao ^{[1
,3
]}

Zhang, Hongqing ^{[2
]}

Feng, Bo ^{[1
,3
]}

Li, Jiaqi ^{[2
]}

Zhang, Yanan ^{[2
]}

Zhang, Ji ^{[2
]}

Zhao, Na ^{[1
,3
]}

Li, Chaoqiang ^{[1
]}

Song, Ning ^{[1
]}

Song, Bin ^{[1
]}

Yang, Dongyuan ^{[4
]}

Chen, Jin ^{[1
,5
,6
]}

Qi, Ao ^{[1
,5
,6
]}

Zhao, Linxiang ^{[3
]}

Luo, Cheng ^{[1
]}

Zang, Yi ^{[1
,4
]}

Liu, Hong ^{[1
]}

Li, Jia ^{[1
,3
,5
]}

Zhang, Bo ^{[2
]}

Zhou, Yu ^{[1
,3
,5
]}

Zheng, Jie ^{[1
,5
,6
,7
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, Key Lab Special Pathogens & Biosafety, Wuhan, Peoples R China

[3] Shenyang Pharmaceut Univ, Shenyang 110016, Peoples R China

[4] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China

[5] UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China

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

[7] Shanghai Jiao Tong Univ, Shanghai Inst Virol, Sch Med, Shanghai 200025, Peoples R China

来源：

ANTIVIRAL RESEARCH | 2024年 / 228卷

基金：

中国国家自然科学基金;

关键词：

PAPAIN-LIKE PROTEASE; RESPIRATORY SYNDROME CORONAVIRUS; NF-KAPPA-B; RIG-I; ADAPTER PROTEIN; INNATE; DEUBIQUITINASE; IDENTIFICATION; PATHWAY; DOMAIN;

D O I：

10.1016/j.antiviral.2024.105944

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

SARS-CoV-2 papain-like protease (PLpro) could facilitate viral replication and host immune evasion by respectively hydrolyzing viral polyprotein and host ubiquitin conjugates, thereby rendering itself as an important antiviral target. Yet few noncovalent PLpro inhibitors of SARS-CoV-2 have been reported with improved directed towards pathogenic deubiquitinating activities inhibition. Herein, we report that coronavirus PLpro proteases have distinctive substrate bias and are conserved to deubiquitylate K63 -linked polyubiquitination, thereby attenuating host type I interferon response. We identify a noncovalent compound specifically optimized towards halting the K63-deubiquitinase activity of SARS-CoV-2 PLpro, but not other coronavirus (CoV) counterparts or host deubiquitinase. Contrasting with GRL0617, a SARS-CoV-1 PLpro inhibitor, SIMM-036 is 50 -fold and 7 -fold (half maximal inhibitory concentration (IC 50 )) more potent to inhibit viral replication during SARS-CoV-2 infection and restore the host interferon- beta (IFN- beta) response in human angiotensin-converting enzyme 2 (hACE2)-HeLa cells, respectively. Structureactivity relationship (SAR) analysis further reveals the importance of BL2 groove of PLpro, which could determine the selectivity of K63-deubiquitinase activity of the enzyme.

引用

页数：12

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