Abstract
The COVID-19 pandemic has shown the urgent need for new treatments for coronavirus infections. Nucleoside analogs have been successfully used to inhibit replication of some viruses, through the incorporation into the growing DNA or RNA chain. However, the replicative machinery of coronaviruses contains nsp14, a a non-structural protein with a 3'→5'-exonuclease activity that removes misincorporated and modified nucleotides from the 3' end of the growing RNA chain. Here we studied the efficiency of hydrolysis of RNA containing various modifications in the 3'-terminal region by SARS-CoV-2 nsp14 exonuclease and its complex with the auxiliary protein nsp10. Single-stranded RNA was a preferable substrate compared to double-stranded, consistent with the model of transfer of the substrate strand to the exonuclease active site proposed on the basis of structural analysis. Modifications of the phosphodiester bond between the penultimate and last nucleotides had the greatest effect on nsp14 activity.
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