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Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections
Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensiv...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594033/ https://www.ncbi.nlm.nih.gov/pubmed/33092055 http://dx.doi.org/10.3390/molecules25204813 |
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author | Bassetto, Marcella Cima, Cecilia M. Basso, Mattia Salerno, Martina Schwarze, Frank Friese, Daniela Bugert, Joachim J. Brancale, Andrea |
author_facet | Bassetto, Marcella Cima, Cecilia M. Basso, Mattia Salerno, Martina Schwarze, Frank Friese, Daniela Bugert, Joachim J. Brancale, Andrea |
author_sort | Bassetto, Marcella |
collection | PubMed |
description | Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism. |
format | Online Article Text |
id | pubmed-7594033 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75940332020-10-30 Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections Bassetto, Marcella Cima, Cecilia M. Basso, Mattia Salerno, Martina Schwarze, Frank Friese, Daniela Bugert, Joachim J. Brancale, Andrea Molecules Article Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism. MDPI 2020-10-20 /pmc/articles/PMC7594033/ /pubmed/33092055 http://dx.doi.org/10.3390/molecules25204813 Text en © 2020 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 Bassetto, Marcella Cima, Cecilia M. Basso, Mattia Salerno, Martina Schwarze, Frank Friese, Daniela Bugert, Joachim J. Brancale, Andrea Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title | Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title_full | Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title_fullStr | Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title_full_unstemmed | Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title_short | Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections |
title_sort | novel nucleoside analogues as effective antiviral agents for zika virus infections |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594033/ https://www.ncbi.nlm.nih.gov/pubmed/33092055 http://dx.doi.org/10.3390/molecules25204813 |
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