6-Substituted 7-Deazapurine Ribonucleosides Capable of Non-canonical Base Recognition as Inhibitors of Respiratory RNA Viruses.

Most nucleoside antiviral analogues mimic canonical Watson-Crick base pairing to increase their likelihood of recognition and incorporation by replicative enzymes into a growing viral nucleic acid strand. Herein, we investigated whether non-canonical base recognition principles based on either shape complementarity or non-hydrogen bond interactions could also be exploited to generate novel small-molecule antivirals. Thus, the exogenous amino group of 7-deazaadenosine was systematically replaced with various 6-alkyl and 6-alkynyl substituents to assess their impact on antiviral activity against RNA respiratory viruses, including influenza A and B, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV). Sub-micromolar potency was observed for multiple compounds, with minimal cytotoxicity and inhibition of host DNA polymerases. Notably, the different modifications profoundly affected the antiviral spectrum, suggesting that despite lacking a hydrogen-bond donor, analogues with either 6-alkyl or 6-alkynyl substituents likely engage polymerases through distinct recognition mechanisms.