Mechanistic insights into coronavirus inhibition by a distinct base-modified adenosine analog targeting the viral polymerase

6-ethyl-modified 7-deazaadenosine (EDA) inhibits SARS-CoV-2 RNA-dependent RNA polymerase by immediate stalling linked to its 6-ethyl base substituent.

• Why it matters: Nucleobase-modified nucleoside analogs are rare and their polymerase inhibition mechanisms are unclear, limiting safe design beyond chain-terminating sugar-modified antivirals.
• What they did: The study used biochemical assays with SARS-CoV-2 RdRp showing EDA-triphosphate mimics ATP, incorporates selectively, stalls RNA synthesis, and is excised by the viral 3'-to-5' exonuclease.
• The result: Cryo-EM showed 3'-terminal EDA fits without template distortion but its 6-ethyl group rearranges the NTP binding pocket to prevent stable incoming nucleotide binding, validated by SARS-CoV-2 RdRp/exonuclease mutant antiviral tests.

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