 Substrate recognition and cleavage mechanism of the monkeypox virus core proteaseYan Gao,
Xiong Xie,
Xiaoyu Zhang,
Junyuan Cao,
Weiqi Lan,
Tian You,
Dongxu Li,
Xuxue Dong,
Wenhao Dai,
Yingchun Xiang,
Shulei Hu,
Weijuan Shang,
Botao Wu,
Yumin Zhang,
Jin Xu,
Xiaoce Liu,
Haofeng Wang,
Wanlong Hu,
Mingjing Zhang,
Yinkai Duan,
Wen Cui,
Hao Zhou,
Shengjiang Mao,
Handi Jia,
Zhanqi Sun,
Menghan Jia,
Yue Yin,
Henry C. Nguyen,
Kailin Yang,
Bei Yang,
Xiuna Yang,
Xiaoyun Ji,
Gengfu Xiao,
Wei Wang (),
Leike Zhang (),
Zihe Rao (),
Hong Liu () and
Haitao Yang ()
Nature, 2025, vol. 643, issue 8070, 271-279 Abstract: Abstract Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (CorePro) is essential for viral maturation and is highly conserved in poxviruses, making it an attractive antiviral target1. However, the structure of CorePro remains unknown, hampering antiviral development. Here we determined the apo structure of monkeypox virus (MPXV) CorePro and the structure of CorePro in a complex with the inhibitor aloxistatin, a drug candidate for muscular dystrophy2. These structures show that CorePro forms a homodimer that features a unique ‘dancing couple’ fold. The catalytic intermediate state of CorePro was characterized by an aldehyde derivative from a natural substrate (I-G18). This derivative binds covalently to the catalytic Cys328, shifting the active site of the viral protease from a closed conformation in the apo form to a favourable open conformation upon substrate binding. On the basis of the CorePro–I-G18 complex, we designed a series of peptidomimetic inhibitors with a nitrile warhead, which could covalently anchor with the catalytic Cys328. These compounds inhibit CorePro with half-maximal inhibitory concentrations of 44.9–100.3 nM, and exhibit potent and broad anti-poxvirus activity. Our studies provide a basis for designing wide-spectrum inhibitors against poxvirus infections. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:643:y:2025:i:8070:d:10.1038_s41586-025-09014-x Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-025-09014-x Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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