Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors
文献类型：期刊论文
| 作者 | Wang, Xudong4,5; Xiong, Liwei1; Zhu, Ying3; Liu, Sixiu4,5; Zhao, Wenfeng4; Wu, Xinyuan4,5; Seydimemet, Mengnisa3; Li, Linjie4; Ding, Peiqi1; Lin, Xian2 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2024-11-22 |
| 页码 | 14 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c12992 |
| 通讯作者 | Mei, Lianghe(meilianghe@susimm.cn) ; Hu, Hangchen(201728012342070@simm.ac.cn) ; Lu, Xiaojie(xjlu@simm.ac.cn) |
| 英文摘要 | The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CLpro, Nsp5) and the papain-like protease (PLpro) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of LU9, a nonpeptide 3CLpro inhibitor with an IC50 of 0.34 mu M, and LU10, whose crystal structure showed a distinct binding mode within the 3CLpro active site. The X-ray cocrystal structure of SARS-CoV-2 PLpro in complex with XD5 uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor XJ5 achieved a potency of 0.12 mu M following comprehensive structure-activity relationship analysis and optimization. Molecular dynamics revealed a potential binding mode. These compounds offer valuable chemical probes for target validation and represent promising candidates for the development of SARS-CoV-2 antiviral therapies. |
| WOS关键词 | PAPAIN-LIKE PROTEASE ; SELECTIVE INHIBITORS ; DESIGN ; POTENT |
| 资助项目 | National Natural Science Foundation of China[32301050] ; National Natural Science Foundation of China (NSFC)[XDB0490000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[23HC1401200] ; Shanghai Action Plan for Science, Technology and Innovation[SIMM0220233001] ; Shanghai Institute of Pharmaceutical Sciences independent research projects[SKLDR-2022-LH-01] ; State Key Laboratory of Drug Research |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001362126900001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314671]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Mei, Lianghe; Hu, Hangchen; Lu, Xiaojie |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Suzhou Inst Chinese Mat Med, Suzhou 215123, Jiangsu, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xudong,Xiong, Liwei,Zhu, Ying,et al. Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024:14. |
| APA | Wang, Xudong.,Xiong, Liwei.,Zhu, Ying.,Liu, Sixiu.,Zhao, Wenfeng.,...&Lu, Xiaojie.(2024).Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,14. |
| MLA | Wang, Xudong,et al."Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2024):14. |
入库方式： OAI收割
来源：上海药物研究所
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