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Viruses. 2019 Apr 20;11(4). pii: E365. doi: 10.3390/v11040365.

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells.

Author information

1
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. jbernatchez@ucsd.edu.
2
Center for Discovery and Innovation in Parasitic Diseases, University of California, San Diego, La Jolla, CA 92093, USA. jbernatchez@ucsd.edu.
3
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. michael.coste1@gmail.com.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. sjbeck@ucsd.edu.
5
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. graceawells@gmail.com.
6
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. luluna@ad.ucsd.edu.
7
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. alexclark@ucsd.edu.
8
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. alexclark@ucsd.edu.
9
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA. zhz504@ucsd.edu.
10
Department of Medicine, Division of Regenerative Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. zhz504@ucsd.edu.
11
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. dhecht@swccd.edu.
12
Department of Chemistry, Southwestern College, Chula Vista, CA 91910, USA. dhecht@swccd.edu.
13
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA. drjeremyrich@gmail.com.
14
Department of Medicine, Division of Regenerative Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. drjeremyrich@gmail.com.
15
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. csohl@sdsu.edu.
16
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA. bpurse@sdsu.edu.
17
The Viral Information Institute, San Diego State University, San Diego, CA 92182, USA. bpurse@sdsu.edu.
18
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. jairlage@ucsd.edu.
19
Center for Discovery and Innovation in Parasitic Diseases, University of California, San Diego, La Jolla, CA 92093, USA. jairlage@ucsd.edu.

Abstract

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 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2'-C-methyluridine and 2'-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2'-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl 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.

KEYWORDS:

NS5; ProTides; RNA-dependent RNA polymerase; Zika virus; antiviral agents; neural stem cells; nucleoside analogues; prodrugs

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