SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
SARS-CoV-2 NSP14, an N7-guanosine methyltransferase, plays a critical role in viral RNA capping, enabling viral replication and immune evasion. While NSP14 has emerged as a promising drug target, its role in host-virus crosstalk and the cellular consequences of NSP14 inhibition remain poorly understood. Here, we present the identification and characterization of C10, a highly potent and selective non-nucleoside inhibitor of the NSP14 S-adenosylmethionine (SAM)-binding pocket. C10 demonstrates robust antiviral activity against SARS-CoV-2, including its variants, with EC<sub>50</sub> values ranging from 64.03 to 301.9 nM, comparable to the FDA-approved drug remdesivir in our cell-based assays. C10 also exhibits broad-spectrum activity against other betacoronaviruses and inhibits SARS-CoV-2 at the replication stage. C10 suppresses viral translation and exhibits immunostimulatory effect. Additionally, C10 specifically reverses NSP14-mediated alterations in host transcriptome. The antiviral efficacy of C10 is further validated in a transgenic mouse model of SARS-CoV-2 infection. Our findings highlight C10 as a promising candidate for the development of effective treatments against SARS-CoV-2 and its emerging variants. This study also uncovers a novel mechanism of NSP14 in SARS-CoV-2 pathogenesis and its therapeutic potential, providing insights that may extend to other viral capping methyltransferases.
Authors
- Huimin Wei (ORCID: https://orcid.org/0000-0002-7989-3803)
- Huan Zhou (ORCID: https://orcid.org/0000-0002-9049-2402)
- Kexin Chen (ORCID: https://orcid.org/0000-0001-6371-4092)
- Xiaowu Dong (ORCID: https://orcid.org/0000-0002-2178-4372)
- Peng Zou (ORCID: https://orcid.org/0000-0002-8223-2600)
- Ziqiao Wang (ORCID: https://orcid.org/0000-0003-3383-8670)
- Yichen Xu (ORCID: https://orcid.org/0009-0004-8423-4150)
- Linjie Li (ORCID: https://orcid.org/0000-0003-4180-4614)
- Wei Xie (ORCID: https://orcid.org/0000-0002-4550-6211)
- Jun Mo
- Ying Wang (ORCID: https://orcid.org/0000-0002-0388-4177)
- Xue Li (ORCID: https://orcid.org/0000-0001-9458-0453)
- Feng Xu (ORCID: https://orcid.org/0000-0002-4670-3727)
- Rong Zhang (ORCID: https://orcid.org/0000-0003-2941-4808)
- Li Shen (ORCID: https://orcid.org/0000-0002-0436-0199)
- Hui Feng (ORCID: https://orcid.org/0009-0000-3192-911X)
- Yongkang Chen (ORCID: https://orcid.org/0000-0002-8070-9858)
- M. X. Luo (ORCID: https://orcid.org/0009-0003-8789-8668)
- Qingwei Zhao (ORCID: https://orcid.org/0000-0002-7201-0588)
- Weihao Chen (ORCID: https://orcid.org/0000-0003-2993-0183)
- Xinyu Wang (ORCID: https://orcid.org/0000-0001-7549-2845)
- Jinxin Che
- Bizhi Li (ORCID: https://orcid.org/0000-0002-7774-5452)
Institutions
- Zhejiang Chinese Medical University (CN)
- Shanghai Medical College of Fudan University (CN)
- Shanghai Public Health Clinical Center (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University of Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s41467-025-64674-7
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Westlake University
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Zhejiang University
- Chinese Academy of Medical Sciences
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences