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Discovery and Improvement of Nucleoside Analogue Prodrugs to Inhibit the RNA Dependent RNA Polymerase of the Zika Virus


Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of ProTides against ZIKV in human neural stem cells and Vero cells. Strong activity was observed for 2’-C-methyluridine and 2’-C-ethynyluridine ProTides with an L-alanine isopropyl ester phenoxy phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate and the POM protecting group for the L-alanine isopropyl ester phenoxy phosphoramidate ProTide group of 2’-C-methyluridine completely abolished antiviral activity of the compound. The L-alanine isopropyl ester phenoxy phosphoramidate ProTide of 2’-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

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