tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Jun Mo[SUP] #[/SUP][SUP] 1 [/SUP], Ziqiao Wang[SUP] #[/SUP][SUP] 2 [/SUP], Huimin Wei[SUP] 1 [/SUP], Kexin Chen[SUP] 1 [/SUP], Liteng Shen[SUP] 1 [/SUP], Ying Wang[SUP] 1 [/SUP], Linjie Li[SUP] 1 [/SUP], Yongkang Chen[SUP] 1 [/SUP], Weihao Chen[SUP] 1 [/SUP], Xue Li[SUP] 1 [/SUP], Hui Feng[SUP] 2 [/SUP], Xinyu Wang[SUP] 1 [/SUP], Huan Zhou[SUP] 1 [/SUP], Bizhi Li[SUP] 1 [/SUP], Feng Xu[SUP] 3 [/SUP], Qingwei Zhao[SUP] 4 [/SUP], Yichen Xu[SUP] 1 [/SUP], Jinxin Che[SUP] 1 5 [/SUP], Peng Zou[SUP] 6 [/SUP], Rong Zhang[SUP] 7 [/SUP], Xiaowu Dong[SUP] 8 9 [/SUP], Wei Xie[SUP] 10 11 [/SUP]
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 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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Jun Mo[SUP] #[/SUP][SUP] 1 [/SUP], Ziqiao Wang[SUP] #[/SUP][SUP] 2 [/SUP], Huimin Wei[SUP] 1 [/SUP], Kexin Chen[SUP] 1 [/SUP], Liteng Shen[SUP] 1 [/SUP], Ying Wang[SUP] 1 [/SUP], Linjie Li[SUP] 1 [/SUP], Yongkang Chen[SUP] 1 [/SUP], Weihao Chen[SUP] 1 [/SUP], Xue Li[SUP] 1 [/SUP], Hui Feng[SUP] 2 [/SUP], Xinyu Wang[SUP] 1 [/SUP], Huan Zhou[SUP] 1 [/SUP], Bizhi Li[SUP] 1 [/SUP], Feng Xu[SUP] 3 [/SUP], Qingwei Zhao[SUP] 4 [/SUP], Yichen Xu[SUP] 1 [/SUP], Jinxin Che[SUP] 1 5 [/SUP], Peng Zou[SUP] 6 [/SUP], Rong Zhang[SUP] 7 [/SUP], Xiaowu Dong[SUP] 8 9 [/SUP], Wei Xie[SUP] 10 11 [/SUP]
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 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.