Development of 3′-Deoxy-3′,4′-didehydro-nucleoside Prodrug Inhibitors of West Nile and Zika Viruses

The antiviral enzyme viperin catalyzes the formation of 3′-deoxy-3′,4′-didehydro-cytidine-5′-triphosphate (ddhCTP). ddhCTP is incorporated into viral genomes and terminates genomic replication to confer broad-spectrum antiviral effects. We have previously utilized phosphoramidate pronucleotide (ProTide) technology to enable metabolic production of ddhCTP in cells from an exogenously dosed 3′-deoxy-3′,4′-didehydro-cytidine ProTide, which confers inhibitory activity against West Nile virus (WNV) and Zika virus (ZIKV). Herein, we synthesized 3′-deoxy-3′,4′-didehydro-nucleosides containing all native nucleobases (thymine, uracil, adenine, guanine, and hypoxanthine), elaborated each to a ProTide, and measured their activity for controlling WNV and ZIKV infection. In comparison to the ddhC ProTide, we found that the ProTides of 3′-deoxy-3′,4′-didehydro-guanosine and 3′-deoxy-3′,4′-didehydro-adenosine possess 2- and 4-fold greater antiviral effects against ZIKV, respectively. Collectively, this work advances the development of 3′-deoxy-3′,4′-didehydro nucleosides as promising compounds for further development into broad-spectrum antiviral agents.