Antiviral Profiling and Cellular Activation of Carbobicyclic Nucleoside Analogues

Nucleoside analogues are important antiviral and anticancer agents. In this study, we investigated a new class of nucleoside analogues built on a synthetically accessible carbobicyclic scaffold designed as a conformational mimic of ribose. Antiviral screening of our library revealed pan-antiviral activity against a range of viruses, including HCV, HSV, and influenza. Structure–activity relationship (SAR) studies highlighted the critical role of the carbocyclic scaffold. The uracil analogue 2a inhibited influenza A virus replication through direct disruption of the viral polymerase, as confirmed by a minigenome assay and further supported by in silico modeling. Importantly, metabolism studies demonstrated that congested C5′–OH is readily phosphorylated without the need for prodrug formulations. The resulting triphosphate metabolites are not substrates of human DNA/RNA polymerases, a primary mechanism of nucleoside drug toxicity. Supported by comprehensive synthetic schemes, we present a carbobicyclic scaffold with altered architecture as a promising chemotype for developing novel nucleoside therapeutics.