Abstract
Bacterial and viral RNA polymerases are promising targets for the development of new transcription inhibitors. One of the potential blockers of RNA synthesis is 7,8-dihydro-8-oxo-1,N6-ethenoadenine (oxo-εA), a synthetic compound that combines two adenine modifications: 8-oxoadenine and 1,N6-ethenoadenine. In this study, we synthesized oxo-εA triphosphate (oxo-εATP) and showed that it could be incorporated by the RNA-dependent RNA polymerase of SARS-CoV-2 into synthesized RNA opposite template residues A and G in the presence of Mn2+ ions. Escherichia coli RNA polymerase incorporated oxo-εATP opposite A residues in the template DNA strand. The presence of oxo-εA instead of adenine in the template DNA strand completely stopped transcription at the modified nucleotide. At the same time, oxo-εATP did not suppress RNA synthesis by both RNA polymerases in the presence of unmodified nucleotides. Therefore, the oxo-εA modification significantly disrupts nucleotide base pairing during RNA synthesis by RNA polymerases of different classes, and the corresponding nucleotide derivatives cannot be used as potential antiviral or antibacterial transcription inhibitors.
Published Version
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