2025-04-11 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202504/t20250411_1041049.shtml
- https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202501625
サル痘ウイルスI7Lプロテアーゼのダイナミックなキャップによる基質アクセスと強力な阻害剤の設計 Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease
Haixia Su, Guoqing Wu, Muya Xiong, Yuhang Wang, Junyuan Cao, Mengyuan You, Yingchun Xiang, Tianqing Nie, Minjun Li, Gengfu Xiao, Leike Zhang, Qiang Shao, Yechun Xu
Advanced Science Published: 07 April 2025
DOI:https://doi.org/10.1002/advs.202501625
Abstract
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.
