Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783418903086497792 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6521205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bernatchezjeana activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT costemichael activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT becksungjun activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT wellsgracea activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT lunalucasa activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT clarkalexe activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT zhuzhe activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT hechtdavid activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT richjeremyn activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT sohlchristald activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT pursebyronw activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells AT siqueiranetojairl activityofselectednucleosideanalogueprotidesagainstzikavirusinhumanneuralstemcells |