tetano
Editor, Senior Moderator
ACS Infect Dis
. 2025 Jul 17.
doi: 10.1021/acsinfecdis.4c01044. Online ahead of print. Identification and Evaluation of Non-Nucleosidic MTase Inhibitors against SARS-CoV-2 nsp14 with Lower-Micromolar Anti-Coronavirus Activity
Yuanmei Wen[SUP] 1 [/SUP], Jun Zhou[SUP] 1 [/SUP], Fan Pan[SUP] 1 [/SUP], Peisen Zheng[SUP] 1 [/SUP], Fengxia Zhong[SUP] 1 [/SUP], Sidi Yang[SUP] 2 [/SUP], Qianhan Ma[SUP] 3 [/SUP], Deyin Guo[SUP] 2 [/SUP], Xumu Zhang[SUP] 1 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Yingjun Li[SUP] 3 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key N7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC[SUB]50[/SUB] = 21.6 μM) and binding affinity (ΔT[SUB]m[/SUB] = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC[SUB]50[/SUB] = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.
Keywords: Coronavirus; Drug screening; Methyltransferase inhibitors; RNA Methylation; nsp14.
. 2025 Jul 17.
doi: 10.1021/acsinfecdis.4c01044. Online ahead of print. Identification and Evaluation of Non-Nucleosidic MTase Inhibitors against SARS-CoV-2 nsp14 with Lower-Micromolar Anti-Coronavirus Activity
Yuanmei Wen[SUP] 1 [/SUP], Jun Zhou[SUP] 1 [/SUP], Fan Pan[SUP] 1 [/SUP], Peisen Zheng[SUP] 1 [/SUP], Fengxia Zhong[SUP] 1 [/SUP], Sidi Yang[SUP] 2 [/SUP], Qianhan Ma[SUP] 3 [/SUP], Deyin Guo[SUP] 2 [/SUP], Xumu Zhang[SUP] 1 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Yingjun Li[SUP] 3 [/SUP]
Affiliations
- PMID: 40674601
- DOI: 10.1021/acsinfecdis.4c01044
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key N7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC[SUB]50[/SUB] = 21.6 μM) and binding affinity (ΔT[SUB]m[/SUB] = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC[SUB]50[/SUB] = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.
Keywords: Coronavirus; Drug screening; Methyltransferase inhibitors; RNA Methylation; nsp14.