A novel, covalent broad-spectrum inhibitor targeting human coronavirus Mpro
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.
Authors
- Jielin Tang (ORCID: https://orcid.org/0000-0002-4398-2927)
- Zhun Li (ORCID: https://orcid.org/0000-0001-8961-9966)
- Jing Sun (ORCID: https://orcid.org/0000-0003-3741-0962)
- Minglei Yang (ORCID: https://orcid.org/0000-0002-6881-337X)
- Chen Zhao (ORCID: https://orcid.org/0000-0003-3217-0269)
- Taotao Li (ORCID: https://orcid.org/0000-0002-7273-5685)
- Jincun Zhao (ORCID: https://orcid.org/0000-0003-2515-5589)
- Yaya Fan (ORCID: https://orcid.org/0000-0002-8880-5094)
- Alex Zhavoronkov (ORCID: https://orcid.org/0000-0001-7067-8966)
- Bogdan Zagribelnyy (ORCID: https://orcid.org/0000-0003-3799-2720)
- Qingsong Zhu
- Xiaoyu Hu (ORCID: https://orcid.org/0000-0003-1384-5005)
- Sang Liu
- Xing Liang (ORCID: https://orcid.org/0000-0002-6630-298X)
- Yan A. Ivanenkov (ORCID: https://orcid.org/0000-0002-8968-0879)
- Maxim N. Malkov (ORCID: https://orcid.org/0009-0009-6642-9401)
- Dmitry S. Bezrukov (ORCID: https://orcid.org/0000-0002-3173-2146)
- Daniil Polykovskiy (ORCID: https://orcid.org/0000-0002-0899-8368)
- Victor A. Terentiev (ORCID: https://orcid.org/0000-0001-7799-9383)
- Alán Aspuru‐Guzik (ORCID: https://orcid.org/0000-0002-8277-4434)
- Peilan Wei
- Guilin Peng
- Deheng Sun (ORCID: https://orcid.org/0009-0004-0082-6918)
- Jingxian Zhao (ORCID: https://orcid.org/0000-0002-2615-3182)
- Airu Zhu (ORCID: https://orcid.org/0000-0002-6374-4467)
- Xinwen Chen (ORCID: https://orcid.org/0000-0002-4052-8155)
- Alexander Aliper (ORCID: https://orcid.org/0000-0002-4363-0710)
- Yiyun He (ORCID: https://orcid.org/0000-0001-5628-4995)
- Man Zhang (ORCID: https://orcid.org/0000-0002-8977-2239)
- Rong Li (ORCID: https://orcid.org/0000-0002-8210-1213)
- Hu Guo (ORCID: https://orcid.org/0000-0003-4503-6501)
- Jie Zheng (ORCID: https://orcid.org/0000-0001-7123-7353)
- Qi Yang (ORCID: https://orcid.org/0009-0009-1648-4189)
- Xiao Ding (ORCID: https://orcid.org/0000-0003-3482-1870)
- Xiaoyu Ding (ORCID: https://orcid.org/0000-0003-2857-8114)
- Xin Cai
- Feng Ren (ORCID: https://orcid.org/0000-0001-9157-9182)
- Bin Yuan (ORCID: https://orcid.org/0000-0002-4021-6186)
- Jingjing Peng
- Jinwei Yuan (ORCID: https://orcid.org/0009-0005-4131-8773)
- Zhanhong Xie
- А. В. Малышев (ORCID: https://orcid.org/0000-0002-5308-1698)
- Xin Guan
- Jingyi Su
- Dong Wang (ORCID: https://orcid.org/0000-0003-4415-1102)
Institutions
- China Executive Leadership Academy Pudong (CN)
- Hong Kong Science and Technology Parks Corporation (HK)
- ShanghaiTech University (CN)
- Guangzhou Experimental Station (CN)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Insilicos (United States) (US)
- Vector Institute (CA)
- Insilicogen (South Korea) (KR)
- Jordan Valley Semiconductors (China) (CN)
- Shenzhen Third People’s Hospital (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1038/s41467-025-59870-4
- Citations
- 17
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 23.73
Funders
- Amazon Web Services
- National Natural Science Foundation of China
- Higher Education Discipline Innovation Project
- Basic and Applied Basic Research Foundation of Guangdong Province