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

文献类型：期刊论文

作者Wang, Qian2,3; Chen, Guofeng3,4; He, Jian3,4; Li, Jiameng2,3; Xiong, Muya3,4; Su, Haixia3; Li, Minjun1; Hu, Hangchen5; Xu, Yechun2,3,4,5
刊名INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
出版日期2023-05-11
卷号24期号:10页码:15
ISSN号1661-6596
关键词SARS-CoV-2 papain-like protease covalent inhibitor co-crystal structure in vitro assay
DOI10.3390/ijms24108633
通讯作者Hu, Hangchen(hangchenhu@ucas.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要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.
WOS关键词CORONAVIRUS
资助项目National Natural Science Foundation of China[22277130] ; Lingang Laboratory[LG-QS-202205-02] ; Science and Technology Commission of Shanghai Municipality[20430780300]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
出版者MDPI
WOS记录号WOS:000998032700001
源URL[http://119.78.100.183/handle/2S10ELR8/306287]  
专题新药研究国家重点实验室
通讯作者Hu, Hangchen; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Qian,Chen, Guofeng,He, Jian,et al. Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2023,24(10):15.
APA Wang, Qian.,Chen, Guofeng.,He, Jian.,Li, Jiameng.,Xiong, Muya.,...&Xu, Yechun.(2023).Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,24(10),15.
MLA Wang, Qian,et al."Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 24.10(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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