tetano
Editor, Senior Moderator
J Gen Virol
. 2025 Dec;106(12).
doi: 10.1099/jgv.0.002190. Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3'-5' exoribonuclease
Victoria Easton[SUP] 1 [/SUP], Martin J McPhillie[SUP] 2 [/SUP], Igor Andrade Santos[SUP] 1 3 [/SUP], Philippa Hall[SUP] 1 [/SUP], C Patrick McClure[SUP] 4 [/SUP], Stuart Astbury[SUP] 5 [/SUP], Emanuelle Paci[SUP] 1 6 [/SUP], Alexander St John[SUP] 1 7 [/SUP], Colin W G Fishwick[SUP] 2 [/SUP], Mark Harris[SUP] 1 [/SUP]
Affiliations
Coronaviruses such as SARS-CoV-2 possess the largest positive-sense RNA virus genomes (30 kb). This poses a fidelity problem as the inherent lack of proof-reading capacity of the viral RNA-dependent RNA polymerase results in a high level of mutation. To overcome this issue, coronaviruses encode a 3'-5' exoribonuclease (ExoN) proof-reading activity, which is a property of a complex of two non-structural proteins nsp14 and nsp10. Inactivating ExoN mutants in SARS-CoV-2 are lethal, indicating the importance of this enzymatic activity for virus replication and raising the possibility that small-molecule inhibitors of ExoN activity could be potential antiviral agents. To evaluate this, we used structure-based drug design approaches to identify potential ExoN inhibitors and tested these for activity against infectious SARS-CoV-2. Two compounds had low micromolar EC[SUB]50[/SUB] activity and synergized with mutagenic nucleoside analogues. Next-generation sequencing analysis revealed an increased rate of mutation in the presence of these compounds, which is consistent with their mode of action being inhibition of ExoN enzymatic activity.
Keywords: SARS-CoV-2; exoribonuclease; nsp14; small molecule inhibitors.
. 2025 Dec;106(12).
doi: 10.1099/jgv.0.002190. Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3'-5' exoribonuclease
Victoria Easton[SUP] 1 [/SUP], Martin J McPhillie[SUP] 2 [/SUP], Igor Andrade Santos[SUP] 1 3 [/SUP], Philippa Hall[SUP] 1 [/SUP], C Patrick McClure[SUP] 4 [/SUP], Stuart Astbury[SUP] 5 [/SUP], Emanuelle Paci[SUP] 1 6 [/SUP], Alexander St John[SUP] 1 7 [/SUP], Colin W G Fishwick[SUP] 2 [/SUP], Mark Harris[SUP] 1 [/SUP]
Affiliations
- PMID: 41417636
- DOI: 10.1099/jgv.0.002190
Coronaviruses such as SARS-CoV-2 possess the largest positive-sense RNA virus genomes (30 kb). This poses a fidelity problem as the inherent lack of proof-reading capacity of the viral RNA-dependent RNA polymerase results in a high level of mutation. To overcome this issue, coronaviruses encode a 3'-5' exoribonuclease (ExoN) proof-reading activity, which is a property of a complex of two non-structural proteins nsp14 and nsp10. Inactivating ExoN mutants in SARS-CoV-2 are lethal, indicating the importance of this enzymatic activity for virus replication and raising the possibility that small-molecule inhibitors of ExoN activity could be potential antiviral agents. To evaluate this, we used structure-based drug design approaches to identify potential ExoN inhibitors and tested these for activity against infectious SARS-CoV-2. Two compounds had low micromolar EC[SUB]50[/SUB] activity and synergized with mutagenic nucleoside analogues. Next-generation sequencing analysis revealed an increased rate of mutation in the presence of these compounds, which is consistent with their mode of action being inhibition of ExoN enzymatic activity.
Keywords: SARS-CoV-2; exoribonuclease; nsp14; small molecule inhibitors.