Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease
文献类型：期刊论文
| 作者 | Su, Haixia1,8; Wu, Guoqing2,9; Xiong, Muya3; Wang, Yuhang4; Cao, Junyuan5,6; You, Mengyuan8; Xiang, Yingchun6; Nie, Tianqing2,9; Li, Minjun7; Xiao, Gengfu5 |
| 刊名 | ADVANCED SCIENCE
 |
| 出版日期 | 2025-04-07 |
| 页码 | 13 |
| 关键词 | covalent inhibitors I7L protease monkeypox virus protein structures substrate proteolysis |
| DOI | 10.1002/advs.202501625 |
| 英文摘要 | Monkeypox virus (MPXV), an orthopoxvirus that has long been endemic in Africa, has posed a significant global health threat since 2022. The I7L protease, a highly conserved cysteine proteinase essential for orthopoxvirus replication, represents a promising target for broad-spectrum antiviral drug development. Here, the first crystal structure of MPXV I7L protease is reported, revealing its unique dimeric form and different conformations of a cap region nearby the active site. Molecular dynamics simulations and AlphaFold3 prediction of protease-substrate structures both suggest that this highly flexible cap acts as a conformational switch, regulating the substrate access to the active site. Additionally, the structural basis of substrate recognition and the catalytic mechanism of the protease are elucidated, mapping determinants of substrate specificity. These insights enable us to design covalent inhibitors to mimic the natural substrates and develop a fluorescence resonance energy transfer (FRET)-based protease assay to effectively assess the inhibitory activity, leading to the discovery of first-in-class inhibitors of MPXV I7L protease with nanomolar potency. Therefore, this work provides a comprehensive understanding of the MPXV I7L protease's structure, dynamics, and function, and presents an example of successful rational design of covalent peptidomimetic inhibitors, serving as a good starting point for drug development against MPXV. |
| WOS关键词 | VACCINIA ; SARS-COV-2 ; BOCEPREVIR ; PROTEINASE ; HIV-1 |
| 资助项目 | National Natural Science Foundation of China ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; Research Program of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SKLDR-2024-TT-03] ; Research Program of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231006] ; National Key Research and Development Plan of China[2022YFC2303300] ; Major Project of Guangzhou National Laboratory[GZNL2024A01008] ; Key R&D Program of Hubei Province[2021BCD004] ; [22307133] ; [22277130] ; [32471306] |
| WOS研究方向 | Chemistry ; Science & Technology - Other Topics ; Materials Science |
| 语种 | 英语 |
| WOS记录号 | WOS:001460494300001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316938]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Leike; Shao, Qiang; Xu, Yechun |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China 3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 5.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, CAS Key Lab Special Pathogens, Wuhan 430064, Peoples R China 6.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China 7.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201204, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 9.Lingang Lab, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Su, Haixia,Wu, Guoqing,Xiong, Muya,et al. Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease[J]. ADVANCED SCIENCE,2025:13. |
| APA | Su, Haixia.,Wu, Guoqing.,Xiong, Muya.,Wang, Yuhang.,Cao, Junyuan.,...&Xu, Yechun.(2025).Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease.ADVANCED SCIENCE,13. |
| MLA | Su, Haixia,et al."Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease".ADVANCED SCIENCE (2025):13. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。