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

Author

Listed:
  • Jing Sun

    (Guangzhou Medical University
    Guangzhou Medical University)

  • Deheng Sun

    (Changtai Plaza)

  • Qi Yang

    (Guangzhou Medical University
    Guangzhou International Bio Island)

  • Dong Wang

    (Guangzhou Medical University
    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
    Guangzhou International Bio Island)

  • 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
    Guangzhou Medical University
    Guangzhou International Bio Island)

  • Nanshan Zhong

    (Guangzhou Medical University
    Guangzhou International Bio Island)

  • Feng Ren

    (Changtai Plaza)

  • Xinwen Chen

    (Guangzhou International Bio Island)

  • Alex Zhavoronkov

    (Changtai Plaza
    IRENA HQ Building)

  • Jincun Zhao

    (Guangzhou Medical University
    Guangzhou Medical University
    Guangzhou International Bio Island
    Shanghai Tech University)

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.

Suggested Citation

  • 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 & , 2025. "A novel, covalent broad-spectrum inhibitor targeting human coronavirus Mpro," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59870-4
    DOI: 10.1038/s41467-025-59870-4
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    References listed on IDEAS

    as
    1. Da-Yuan Chen & Chue Vin Chin & Devin Kenney & Alexander H. Tavares & Nazimuddin Khan & Hasahn L. Conway & GuanQun Liu & Manish C. Choudhary & Hans P. Gertje & Aoife K. O’Connell & Scott Adams & Darrel, 2023. "Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation," Nature, Nature, vol. 615(7950), pages 143-150, March.
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