SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

  • Nat Commun. 2025 Nov 3;16(1):9671. doi: 10.1038/s41467-025-64674-7.
Mengxin Luo  #  1 ,  Jun Mo  #  1 ,  Ziqiao Wang  #  2 ,  Huimin Wei  1 ,  Kexin Chen  1 ,  Liteng Shen  1 ,  Ying Wang  1 ,  Linjie Li  1 ,  Yongkang Chen  1 ,  Weihao Chen  1 ,  Xue Li  1 ,  Hui Feng  2 ,  Xinyu Wang  1 ,  Huan Zhou  1 ,  Bizhi Li  1 ,  Feng Xu  3 ,  Qingwei Zhao  4 ,  Yichen Xu  1 ,  Jinxin Che  1  5 ,  Peng Zou  6 ,  Rong Zhang  7 ,  Xiaowu Dong  8  9 ,  Wei Xie  10  11
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4. Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5. Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 6. Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
  • 7. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 8. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 10. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
  • 11. Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41184286 DOI: 10.1038/s41467-025-64674-7
Abstract

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 EC50 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.

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