A novel, covalent broad-spectrum inhibitor targeting human coronavirus Mpro

Jing Sun, Deheng Sun, Qi Yang, Dong Wang, Jingjing Peng, Hu Guo, Xiaoyu Ding, Zhao Chen, Bin Yuan, Yan A. Ivanenkov, Jinwei Yuan, Bogdan A. Zagribelnyy, Yiyun He, Jingyi Su, Ling Wang, Jielin Tang, Zhun Li, Rong Li, Taotao Li, Xiaoyu Hu, Xing Liang, Airu Zhu, Peilan Wei, Yaya Fan, Sang Liu, Jie Zheng, Xin Guan, Alex Aliper, Minglei Yang, Dmitry S. Bezrukov, Zhanhong Xie, Victor A. Terentiev, Guilin Peng, Daniil A. Polykovskiy, Alexander S. Malyshev, Maxim N. Malkov, Qingsong Zhu, Alán Aspuru-Guzik, Xiao Ding, Xin Cai, Man Zhang, Jingxian Zhao (), Nanshan Zhong (), Feng Ren (), Xinwen Chen (), Alex Zhavoronkov () and Jincun Zhao ()
Additional contact information
Jing Sun: Guangzhou Medical University
Deheng Sun: Changtai Plaza
Qi Yang: Guangzhou Medical University
Dong Wang: Guangzhou Medical University
Jingjing Peng: Changtai Plaza
Hu Guo: Guangzhou Medical University
Xiaoyu Ding: Changtai Plaza
Zhao Chen: Guangzhou Medical University
Bin Yuan: Guangzhou Medical University
Yan A. Ivanenkov: Hong Kong
Jinwei Yuan: Guangzhou Medical University
Bogdan A. Zagribelnyy: IRENA HQ Building
Yiyun He: Guangzhou Medical University
Jingyi Su: Guangzhou Medical University
Ling Wang: Changtai Plaza
Jielin Tang: Guangzhou Medical University
Zhun Li: Guangzhou Medical University
Rong Li: Shanghai Tech University
Taotao Li: Changtai Plaza
Xiaoyu Hu: Guangzhou Medical University
Xing Liang: Changtai Plaza
Airu Zhu: Guangzhou Medical University
Peilan Wei: Guangzhou Medical University
Yaya Fan: Changtai Plaza
Sang Liu: Changtai Plaza
Jie Zheng: Guangzhou Medical University
Xin Guan: Guangzhou Medical University
Alex Aliper: IRENA HQ Building
Minglei Yang: Shanghai Tech University
Dmitry S. Bezrukov: IRENA HQ Building
Zhanhong Xie: Guangzhou Medical University
Victor A. Terentiev: Hong Kong
Guilin Peng: Guangzhou Medical University
Daniil A. Polykovskiy: 3710-1250 Ren´e-L´evesque west
Alexander S. Malyshev: Hong Kong
Maxim N. Malkov: IRENA HQ Building
Qingsong Zhu: IRENA HQ Building
Alán Aspuru-Guzik: Canadian Institute for Advanced Research
Xiao Ding: Changtai Plaza
Xin Cai: Changtai Plaza
Man Zhang: Changtai Plaza
Jingxian Zhao: Guangzhou Medical University
Nanshan Zhong: Guangzhou Medical University
Feng Ren: Changtai Plaza
Xinwen Chen: Guangzhou International Bio Island
Alex Zhavoronkov: Changtai Plaza
Jincun Zhao: Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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 (Mpro) 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 Mpro. ISM3312 is identified as an irreversible, covalent Mpro 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 Mpro 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.

Date: 2025
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DOI: 10.1038/s41467-025-59870-4

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