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.