biostudies-literatureKennelly SAUniversity of MinnesotaNational Cancer InstituteNCI NIH HHS1334-1339https://www.ebi.ac.uk/biostudies/studies/S-EPMC11318099biostudies-literatureUnknown15(8)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 ProTiACS medicinal chemistry lettersDevelopment of 3'-Deoxy-3',4'-didehydro-nucleoside Prodrug Inhibitors of West Nile and Zika Viruses.PMC11318099P30-CA77598P30 CA077598293501Sawyer JMPayne AFCiota ATHarki DAKennelly SAfalseDevelopment 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 ProTi2024-01-01T00:00:00Z2024 Aug2026-04-12T19:24:28.025Z2026-04-07T13:17:29.201ZS-EPMC113180993914004610.1021/acsmedchemlett.4c00225