tetano
Editor, Senior Moderator
Bioorg Chem
. 2024 Oct 18:153:107894.
doi: 10.1016/j.bioorg.2024.107894. Online ahead of print. Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection
Qishu Chen[SUP] 1 [/SUP], Qifan Zhou[SUP] 2 [/SUP], Sidi Yang[SUP] 3 [/SUP], Fan Pan[SUP] 1 [/SUP], Hongqi Tao[SUP] 1 [/SUP], Yuanmei Wen[SUP] 1 [/SUP], Yang Chao[SUP] 1 [/SUP], Cailing Xie[SUP] 3 [/SUP], Weixin Ou[SUP] 3 [/SUP], Deyin Guo[SUP] 4 [/SUP], Yingjun Li[SUP] 5 [/SUP], Xumu Zhang[SUP] 6 [/SUP]
Affiliations
Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC[SUB]50[/SUB] of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.
Keywords: Anti-coronavirus; Combination therapy; Coronavirus; Immune escape; nsp14 MTase inhibitor.
. 2024 Oct 18:153:107894.
doi: 10.1016/j.bioorg.2024.107894. Online ahead of print. Identification of adenosine analogues as nsp14 N7‑methyltransferase inhibitors for treating coronaviruses infection
Qishu Chen[SUP] 1 [/SUP], Qifan Zhou[SUP] 2 [/SUP], Sidi Yang[SUP] 3 [/SUP], Fan Pan[SUP] 1 [/SUP], Hongqi Tao[SUP] 1 [/SUP], Yuanmei Wen[SUP] 1 [/SUP], Yang Chao[SUP] 1 [/SUP], Cailing Xie[SUP] 3 [/SUP], Weixin Ou[SUP] 3 [/SUP], Deyin Guo[SUP] 4 [/SUP], Yingjun Li[SUP] 5 [/SUP], Xumu Zhang[SUP] 6 [/SUP]
Affiliations
- PMID: 39490138
- DOI: 10.1016/j.bioorg.2024.107894
Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC[SUB]50[/SUB] of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.
Keywords: Anti-coronavirus; Combination therapy; Coronavirus; Immune escape; nsp14 MTase inhibitor.