Structure-guided discovery of a small molecule inhibitor of SARS-CoV-2 main protease with potent <i>in vitro</i> and <i>in vivo</i> antiviral activities
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M<sup>pro</sup>) is a clinically validated target for the treatment of coronavirus disease 2019 (COVID-19). Here, we report the hit-to-lead discovery of a new nitrile-based inhibitor, <b>H135</b>, of SARS-CoV-2 M<sup>pro</sup> from a series of chemical modifications of a nitrile-warhead-containing compound guided by its 1.8 Å high-resolution crystal structure in complex with SARS-CoV-2 M<sup>pro</sup>. <b>H135</b> exhibited potent and selective inhibition of SARS-CoV-2 M<sup>pro</sup> with IC<sub>50</sub> of 12.7 nM and exerted broad anti-SARS-CoV-2 activity in VeroE6-TMPRSS2 cells. Furthermore, <b>H135</b>-treated golden Syrian hamsters demonstrated significantly lower respiratory tract viral burden compared with solvent-treated control hamsters. <b>H135</b> may serve as a new lead for developing antiviral therapeutics for SARS-CoV-2 infection.IMPORTANCEIn this study, a structure-guided hit-to-lead strategy was employed to develop a nanomolar potent small molecule inhibitor H135 of SARS-CoV-2 M<sup>pro</sup> with strong anti-SARS-CoV-2 infection activity in cell cultures and animals. H135 may serve as a new lead for developing antiviral agents targeting the virus's main protease M<sup>pro</sup>.
Authors
- Vincent Kwok‐Man Poon (ORCID: https://orcid.org/0000-0002-7737-8912)
- Chris Chung‐Sing Chan (ORCID: https://orcid.org/0000-0001-7089-4829)
- Yubin Xie
- Shuofeng Yuan (ORCID: https://orcid.org/0000-0001-7996-1119)
- Xiaohong Sang (ORCID: https://orcid.org/0009-0002-6561-2254)
- Pu Han (ORCID: https://orcid.org/0000-0002-1417-7718)
- Jasper Fuk‐Woo Chan (ORCID: https://orcid.org/0000-0001-6336-6657)
- Meixian Wu
- Lina Huang (ORCID: https://orcid.org/0000-0002-2921-6097)
- Yong Feng (ORCID: https://orcid.org/0000-0003-1590-0186)
- Lifeng Fu (ORCID: https://orcid.org/0000-0003-0431-5424)
- Jianxun Qi (ORCID: https://orcid.org/0000-0002-9358-4732)
- Juan Wang (ORCID: https://orcid.org/0009-0009-7530-1274)
- Wenyan Zheng
- Ziwei Huang (ORCID: https://orcid.org/0000-0001-5459-1211)
- Jing An (ORCID: https://orcid.org/0000-0003-3865-2269)
- Xu Yan (ORCID: https://orcid.org/0009-0002-0051-8718)
- Kwok-Yung Yuen (ORCID: https://orcid.org/0000-0001-8700-4570)
- Jiao Zhou (ORCID: https://orcid.org/0000-0002-4015-427X)
- Kenn Ka-Heng Chik
- Jessica Oi‐Ling Tsang
Institutions
- Guangxi University (CN)
- Chinese Academy of Sciences (CN)
- Queen Mary Hospital (CN)
- Hong Kong Science and Technology Parks Corporation (HK)
- University of California System (US)
- University of California San Diego (US)
- Hong Kong Association of Registered Tour Co-ordinators (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- AgroBio (BR)
- Institute of Microbiology (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- State Key Laboratory For Conservation and Utilization of Subtropical Agro-Bioresources (CN)
- Hainan Medical University (CN)
- University of Hong Kong (HK)
- Tsinghua University (CN)
Publication Details
- Journal
- Journal of Virology
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1128/jvi.01001-25
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40