Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease
文献类型：期刊论文
| 作者 | Hu, Hangchen2,3,4; Wang, Qian1; Su, Haixia3; Shao, Qiang3 ; Zhao, Wenfeng3; Chen, Guofeng3,4; Li, Minjun5; Xu, Yechun1,2,3,4
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| 刊名 | ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
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| 出版日期 | 2022-11-28 |
| 页码 | 10 |
| 关键词 | Allosteric Modulator Cysteine 270 Drug Design Papain-Like Protease SARS-CoV-2 |
| ISSN号 | 1433-7851 |
| DOI | 10.1002/anie.202212378 |
| 通讯作者 | Li, Minjun(liminjun@zjlab.org.cn) ; Xu, Yechun(ycxu@simm.ac.cn) |
| 英文摘要 | The coronavirus papain-like protease (PLpro) plays an important role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. However, the development of inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro is challenging owing to the restricted S1/S2 sites in the substrate binding pocket. Here we report the discovery of two activators of SARS-CoV-2 PLpro and the identification of the unique residue, cysteine 270 (C270), as an allosteric and covalent regulatory site for the activators. This site is also specifically modified by glutathione, resulting in protease activation. Furthermore, a compound was found to allosterically inhibit the protease activity by covalent binding to C270. Together, these results elucidate an unrevealed molecular mechanism for allosteric modulation of SARS-CoV-2 PLpro and provid a novel site for allosteric inhibitors design. |
| WOS关键词 | RESPIRATORY SYNDROME CORONAVIRUS ; GLUTATHIONE |
| 资助项目 | National Natural Science Foundation of China[22277130] ; National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[32071248] ; Science and Technology Commission of Shanghai Municipality[20430780300] ; Science and Technology Commission of Shanghai Municipality[TM202101H003] ; Qiusuo Outstanding Youth Project of Lingang Laboratory[LG-QS-202205-02] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000891159200001 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304407]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Minjun; Xu, Yechun |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hu, Hangchen,Wang, Qian,Su, Haixia,et al. Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2022:10. |
| APA | Hu, Hangchen.,Wang, Qian.,Su, Haixia.,Shao, Qiang.,Zhao, Wenfeng.,...&Xu, Yechun.(2022).Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,10. |
| MLA | Hu, Hangchen,et al."Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2022):10. |
入库方式： OAI收割
来源：上海药物研究所
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