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

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 in...

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Autores principales: Bernatchez, Jean A., Coste, Michael, Beck, Sungjun, Wells, Grace A., Luna, Lucas A., Clark, Alex E., Zhu, Zhe, Hecht, David, Rich, Jeremy N., Sohl, Christal D., Purse, Byron W., Siqueira-Neto, Jair L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521205/
https://www.ncbi.nlm.nih.gov/pubmed/31010044
http://dx.doi.org/10.3390/v11040365
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author Bernatchez, Jean A.
Coste, Michael
Beck, Sungjun
Wells, Grace A.
Luna, Lucas A.
Clark, Alex E.
Zhu, Zhe
Hecht, David
Rich, Jeremy N.
Sohl, Christal D.
Purse, Byron W.
Siqueira-Neto, Jair L.
author_facet Bernatchez, Jean A.
Coste, Michael
Beck, Sungjun
Wells, Grace A.
Luna, Lucas A.
Clark, Alex E.
Zhu, Zhe
Hecht, David
Rich, Jeremy N.
Sohl, Christal D.
Purse, Byron W.
Siqueira-Neto, Jair L.
author_sort Bernatchez, Jean A.
collection PubMed
description 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.
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spelling pubmed-65212052019-06-03 Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells Bernatchez, Jean A. Coste, Michael Beck, Sungjun Wells, Grace A. Luna, Lucas A. Clark, Alex E. Zhu, Zhe Hecht, David Rich, Jeremy N. Sohl, Christal D. Purse, Byron W. Siqueira-Neto, Jair L. Viruses Article 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. MDPI 2019-04-20 /pmc/articles/PMC6521205/ /pubmed/31010044 http://dx.doi.org/10.3390/v11040365 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bernatchez, Jean A.
Coste, Michael
Beck, Sungjun
Wells, Grace A.
Luna, Lucas A.
Clark, Alex E.
Zhu, Zhe
Hecht, David
Rich, Jeremy N.
Sohl, Christal D.
Purse, Byron W.
Siqueira-Neto, Jair L.
Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title_full Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title_fullStr Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title_full_unstemmed Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title_short Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
title_sort activity of selected nucleoside analogue protides against zika virus in human neural stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521205/
https://www.ncbi.nlm.nih.gov/pubmed/31010044
http://dx.doi.org/10.3390/v11040365
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