tetano
Editor, Senior Moderator
Nat Commun
. 2025 May 15;16(1):4546.
doi: 10.1038/s41467-025-59870-4. A novel, covalent broad-spectrum inhibitor targeting human coronavirus M[SUP]pro[/SUP]
Jing Sun[SUP] #[/SUP][SUP] 1 2 [/SUP], Deheng Sun[SUP] #[/SUP][SUP] 3 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 1 4 [/SUP], Dong Wang[SUP] #[/SUP][SUP] 1 5 [/SUP], Jingjing Peng[SUP] #[/SUP][SUP] 3 [/SUP], Hu Guo[SUP] #[/SUP][SUP] 1 [/SUP], Xiaoyu Ding[SUP] #[/SUP][SUP] 3 [/SUP], Zhao Chen[SUP] 1 [/SUP], Bin Yuan[SUP] 1 [/SUP], Yan A Ivanenkov[SUP] 6 [/SUP], Jinwei Yuan[SUP] 1 [/SUP], Bogdan A Zagribelnyy[SUP] 7 [/SUP], Yiyun He[SUP] 1 [/SUP], Jingyi Su[SUP] 1 [/SUP], Ling Wang[SUP] 3 [/SUP], Jielin Tang[SUP] 1 4 [/SUP], Zhun Li[SUP] 1 [/SUP], Rong Li[SUP] 8 [/SUP], Taotao Li[SUP] 3 [/SUP], Xiaoyu Hu[SUP] 1 [/SUP], Xing Liang[SUP] 3 [/SUP], Airu Zhu[SUP] 1 [/SUP], Peilan Wei[SUP] 1 [/SUP], Yaya Fan[SUP] 3 [/SUP], Sang Liu[SUP] 3 [/SUP], Jie Zheng[SUP] 1 [/SUP], Xin Guan[SUP] 1 [/SUP], Alex Aliper[SUP] 7 [/SUP], Minglei Yang[SUP] 8 [/SUP], Dmitry S Bezrukov[SUP] 7 [/SUP], Zhanhong Xie[SUP] 1 [/SUP], Victor A Terentiev[SUP] 6 [/SUP], Guilin Peng[SUP] 1 [/SUP], Daniil A Polykovskiy[SUP] 9 [/SUP], Alexander S Malyshev[SUP] 6 [/SUP], Maxim N Malkov[SUP] 7 [/SUP], Qingsong Zhu[SUP] 7 [/SUP], Alán Aspuru-Guzik[SUP] 10 [/SUP], Xiao Ding[SUP] 3 [/SUP], Xin Cai[SUP] 3 [/SUP], Man Zhang[SUP] 3 [/SUP], Jingxian Zhao[SUP] 11 12 13 [/SUP], Nanshan Zhong[SUP] 14 15 [/SUP], Feng Ren[SUP] 16 [/SUP], Xinwen Chen[SUP] 17 [/SUP], Alex Zhavoronkov[SUP] 18 19 [/SUP], Jincun Zhao[SUP] 20 21 22 23 24 [/SUP]
Affiliations
Human coronaviruses (CoV) cause respiratory infections that range from mild to severe. CoVs are a large family of viruses with considerable genetic heterogeneity and a multitude of viral types, making preventing and treating these viruses difficult. Comprehensive treatments that inhibit CoV infections fulfill a pressing medical need and may be immensely valuable in managing emerging and endemic CoV infections. As the main protease (M[SUP]pro[/SUP]) is highly conserved across many CoVs, this protease has been identified as a route for broad CoV inhibition. We utilize the advanced generative chemistry platform Chemistry42 for de novo molecular design and obtained novel small-molecule, non-peptide-like inhibitors targeting the SARS-CoV-2 M[SUP]pro[/SUP]. ISM3312 is identified as an irreversible, covalent M[SUP]pro[/SUP] inhibitor from extensive virtual screening and structure-based optimization efforts. ISM3312 exhibits low off-target risk and outstanding antiviral activity against multiple human coronaviruses, including SARS-CoV-2, MERS-CoV, 229E, OC43, NL63, and HKU1 independent of P-glycoprotein (P-gp) inhibition. Furthermore, ISM3312 shows significant inhibitory effects against Nirmatrelvir-resistant M[SUP]pro[/SUP] mutants, suggesting ISM3312 may contribute to reduced viral escape in these settings. Incorporating ISM3312 and Nirmatrelvir into antiviral strategy could improve preparedness and reinforce defenses against future coronavirus threats.
. 2025 May 15;16(1):4546.
doi: 10.1038/s41467-025-59870-4. A novel, covalent broad-spectrum inhibitor targeting human coronavirus M[SUP]pro[/SUP]
Jing Sun[SUP] #[/SUP][SUP] 1 2 [/SUP], Deheng Sun[SUP] #[/SUP][SUP] 3 [/SUP], Qi Yang[SUP] #[/SUP][SUP] 1 4 [/SUP], Dong Wang[SUP] #[/SUP][SUP] 1 5 [/SUP], Jingjing Peng[SUP] #[/SUP][SUP] 3 [/SUP], Hu Guo[SUP] #[/SUP][SUP] 1 [/SUP], Xiaoyu Ding[SUP] #[/SUP][SUP] 3 [/SUP], Zhao Chen[SUP] 1 [/SUP], Bin Yuan[SUP] 1 [/SUP], Yan A Ivanenkov[SUP] 6 [/SUP], Jinwei Yuan[SUP] 1 [/SUP], Bogdan A Zagribelnyy[SUP] 7 [/SUP], Yiyun He[SUP] 1 [/SUP], Jingyi Su[SUP] 1 [/SUP], Ling Wang[SUP] 3 [/SUP], Jielin Tang[SUP] 1 4 [/SUP], Zhun Li[SUP] 1 [/SUP], Rong Li[SUP] 8 [/SUP], Taotao Li[SUP] 3 [/SUP], Xiaoyu Hu[SUP] 1 [/SUP], Xing Liang[SUP] 3 [/SUP], Airu Zhu[SUP] 1 [/SUP], Peilan Wei[SUP] 1 [/SUP], Yaya Fan[SUP] 3 [/SUP], Sang Liu[SUP] 3 [/SUP], Jie Zheng[SUP] 1 [/SUP], Xin Guan[SUP] 1 [/SUP], Alex Aliper[SUP] 7 [/SUP], Minglei Yang[SUP] 8 [/SUP], Dmitry S Bezrukov[SUP] 7 [/SUP], Zhanhong Xie[SUP] 1 [/SUP], Victor A Terentiev[SUP] 6 [/SUP], Guilin Peng[SUP] 1 [/SUP], Daniil A Polykovskiy[SUP] 9 [/SUP], Alexander S Malyshev[SUP] 6 [/SUP], Maxim N Malkov[SUP] 7 [/SUP], Qingsong Zhu[SUP] 7 [/SUP], Alán Aspuru-Guzik[SUP] 10 [/SUP], Xiao Ding[SUP] 3 [/SUP], Xin Cai[SUP] 3 [/SUP], Man Zhang[SUP] 3 [/SUP], Jingxian Zhao[SUP] 11 12 13 [/SUP], Nanshan Zhong[SUP] 14 15 [/SUP], Feng Ren[SUP] 16 [/SUP], Xinwen Chen[SUP] 17 [/SUP], Alex Zhavoronkov[SUP] 18 19 [/SUP], Jincun Zhao[SUP] 20 21 22 23 24 [/SUP]
Affiliations
- PMID: 40374668
- PMCID: PMC12081877
- DOI: 10.1038/s41467-025-59870-4
Human coronaviruses (CoV) cause respiratory infections that range from mild to severe. CoVs are a large family of viruses with considerable genetic heterogeneity and a multitude of viral types, making preventing and treating these viruses difficult. Comprehensive treatments that inhibit CoV infections fulfill a pressing medical need and may be immensely valuable in managing emerging and endemic CoV infections. As the main protease (M[SUP]pro[/SUP]) is highly conserved across many CoVs, this protease has been identified as a route for broad CoV inhibition. We utilize the advanced generative chemistry platform Chemistry42 for de novo molecular design and obtained novel small-molecule, non-peptide-like inhibitors targeting the SARS-CoV-2 M[SUP]pro[/SUP]. ISM3312 is identified as an irreversible, covalent M[SUP]pro[/SUP] inhibitor from extensive virtual screening and structure-based optimization efforts. ISM3312 exhibits low off-target risk and outstanding antiviral activity against multiple human coronaviruses, including SARS-CoV-2, MERS-CoV, 229E, OC43, NL63, and HKU1 independent of P-glycoprotein (P-gp) inhibition. Furthermore, ISM3312 shows significant inhibitory effects against Nirmatrelvir-resistant M[SUP]pro[/SUP] mutants, suggesting ISM3312 may contribute to reduced viral escape in these settings. Incorporating ISM3312 and Nirmatrelvir into antiviral strategy could improve preparedness and reinforce defenses against future coronavirus threats.