A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide
| Autor: | Alexander T. Ciota, Haley S Caldwell, Anoop Narayanan, Kellan T. Passow, Kiet A. Ngo, Craig E. Cameron, Shana J. Sturla, Jamie J. Arnold, Joyce Jose, Nicole M. Antczak, Daniel A. Harki |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cytidine Triphosphate
Endogeny Microbial Sensitivity Tests Antiviral Agents Article Cell Line Structure-Activity Relationship Drug Discovery Chlorocebus aethiops Animals Humans Nucleotide chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Chemistry Phosphoramidate Zika Virus Prodrug Titer Biochemistry Toxicity Molecular Medicine Nucleoside West Nile virus Intracellular |
| Zdroj: | J Med Chem |
| DOI: | 10.17615/hy4j-3r92 |
| Popis: | 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 non-specific 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. |
| Databáze: | OpenAIRE |
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