Why the study?
The endogenous antiviral nucleotide ddhCTP has potent broad-spectrum activity, but nucleoside 5'-triphosphates are not cell-permeable, precluding its direct therapeutic use.
Does HLB-0532247 reduce viral titers of Zika and West Nile viruses in cell culture compared to ddhC?
Does HLB-0532247 reduce viral titers of Zika and West Nile viruses in cell culture compared to ddhC?
The phosphoramidate prodrug HLB-0532247 effectively increases intracellular levels of the antiviral nucleotide ddhCTP and reduces Zika and West Nile virus titers in vitro.
May enable therapeutic delivery of ddhCTP; leaves open clinical antiviral efficacy and safety.
The naturally occurring nucleotide 3′-deoxy-3′,4′-didehydro-cytidine-5′-triphosphate ( ddhCTP ) was recently found to exert potent and broad-spectrum antiviral activity. However, nucleoside 5′-triphosphates in general are not cell-permeable, which precludes the direct use of ddhCTP as a therapeutic. To harness the therapeutic potential of this endogenous antiviral nucleotide, we synthesized phosphoramidate prodrug HLB-0532247 ( 1 ) and found it to result in dramatically elevated levels of ddhCTP in cells. We compared 1 and 3′-deoxy-3′,4′-didehydro-cytidine ( ddhC ) and found that 1 more effectively reduces titers of Zika and West Nile viruses in cell culture with minimal nonspecific toxicity to host cells. We conclude that 1 is a promising antiviral agent based on a novel strategy of facilitating elevated levels of the endogenous ddhCTP antiviral nucleotide.
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Passow et al. (2021) studied Zika and West Nile viruses. Phosphoramidate prodrug HLB-0532247 (1) vs. 3′-deoxy-3′,4′-didehydro-cytidine (ddhC) was evaluated on Viral titers of Zika and West Nile viruses in cell culture.
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