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.

J. Med. Chem. 2026, 69, 5, 5501–5539