2. Academic Validation
  3. SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation

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

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. rong_zhang@fudan.edu.cn.
  • 8 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. dongxw@zju.edu.cn.
  • 9 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. dongxw@zju.edu.cn.
  • 10 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. xie_wei@zju.edu.cn.
  • 11 Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. xie_wei@zju.edu.cn.
  • # 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z