tetano
Editor, Senior Moderator
J Virol
. 2025 Nov 14:e0100125.
doi: 10.1128/jvi.01001-25. Online ahead of print. Structure-guided discovery of a small molecule inhibitor of SARS-CoV-2 main protease with potent in vitro and in vivo antiviral activities
Shuofeng Yuan[SUP] #[/SUP][SUP] 1 2 3 4 5 [/SUP], Juan Wang[SUP] #[/SUP][SUP] 6 [/SUP], Xiaohong Sang[SUP] #[/SUP][SUP] 7 [/SUP], Yubin Xie[SUP] #[/SUP][SUP] 1 2 [/SUP], Yong Feng[SUP] #[/SUP][SUP] 8 [/SUP], Vincent Kwok-Man Poon[SUP] 1 2 [/SUP], Chris Chung-Sing Chan[SUP] 1 2 [/SUP], Jessica Oi-Ling Tsang[SUP] 1 2 [/SUP], Kenn Ka-Heng Chik[SUP] 1 2 [/SUP], Jiao Zhou[SUP] 7 [/SUP], Yan Xu[SUP] 9 [/SUP], Pu Han[SUP] 8 [/SUP], Wenyan Zheng[SUP] 8 10 [/SUP], Lifeng Fu[SUP] 8 [/SUP], Lina Sirui Mihara Huang[SUP] 9 [/SUP], Meixian Wu[SUP] 9 [/SUP], Jing An[SUP] 9 [/SUP], Kwok-Yung Yuen[SUP] 1 2 3 4 5 11 12 [/SUP], Jianxun Qi[SUP] 8 [/SUP], Ziwei Huang[SUP] 7 9 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 2 3 4 5 11 12 [/SUP]
Affiliations
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, H135, 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]. H135 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, H135-treated golden Syrian hamsters demonstrated significantly lower respiratory tract viral burden compared with solvent-treated control hamsters. H135 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].
Keywords: SARS-CoV-2; antiviral; protease.
. 2025 Nov 14:e0100125.
doi: 10.1128/jvi.01001-25. Online ahead of print. Structure-guided discovery of a small molecule inhibitor of SARS-CoV-2 main protease with potent in vitro and in vivo antiviral activities
Shuofeng Yuan[SUP] #[/SUP][SUP] 1 2 3 4 5 [/SUP], Juan Wang[SUP] #[/SUP][SUP] 6 [/SUP], Xiaohong Sang[SUP] #[/SUP][SUP] 7 [/SUP], Yubin Xie[SUP] #[/SUP][SUP] 1 2 [/SUP], Yong Feng[SUP] #[/SUP][SUP] 8 [/SUP], Vincent Kwok-Man Poon[SUP] 1 2 [/SUP], Chris Chung-Sing Chan[SUP] 1 2 [/SUP], Jessica Oi-Ling Tsang[SUP] 1 2 [/SUP], Kenn Ka-Heng Chik[SUP] 1 2 [/SUP], Jiao Zhou[SUP] 7 [/SUP], Yan Xu[SUP] 9 [/SUP], Pu Han[SUP] 8 [/SUP], Wenyan Zheng[SUP] 8 10 [/SUP], Lifeng Fu[SUP] 8 [/SUP], Lina Sirui Mihara Huang[SUP] 9 [/SUP], Meixian Wu[SUP] 9 [/SUP], Jing An[SUP] 9 [/SUP], Kwok-Yung Yuen[SUP] 1 2 3 4 5 11 12 [/SUP], Jianxun Qi[SUP] 8 [/SUP], Ziwei Huang[SUP] 7 9 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 2 3 4 5 11 12 [/SUP]
Affiliations
- PMID: 41236503
- DOI: 10.1128/jvi.01001-25
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, H135, 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]. H135 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, H135-treated golden Syrian hamsters demonstrated significantly lower respiratory tract viral burden compared with solvent-treated control hamsters. H135 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].
Keywords: SARS-CoV-2; antiviral; protease.