Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease

被引:5
作者
Wang, Qian [1 ,2 ]
Chen, Guofeng [2 ,3 ]
He, Jian [2 ,3 ]
Li, Jiameng [1 ,2 ]
Xiong, Muya [2 ,3 ]
Su, Haixia [2 ]
Li, Minjun [4 ]
Hu, Hangchen [5 ]
Xu, Yechun [1 ,2 ,3 ,5 ]
机构
[1] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China
[4] Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
[5] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
SARS-CoV-2; papain-like protease; covalent inhibitor; co-crystal structure; in vitro assay; CORONAVIRUS;
D O I
10.3390/ijms24108633
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 papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PLpro. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC50 = 0.23 mu M) and significant inhibition of SARS-CoV-2 PLpro in the HEK293T cells using a cell-based protease assay (EC50 = 3.61 mu M). Moreover, an X-ray crystal structure of SARS-CoV-2 PLpro in complex with compound 2 confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PLpro inhibitors and provide an attractive starting point for further optimization.
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页数:15
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