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Nat Commun
. 2025 Nov 3;16(1):9671.
doi: 10.1038/s41467-025-64674-7. SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
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
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.
. 2025 Nov 3;16(1):9671.
doi: 10.1038/s41467-025-64674-7. SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
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
- PMID: 41184286
- DOI: 10.1038/s41467-025-64674-7
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.