Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Bassetto, Marcella, Cima, Cecilia M., Basso, Mattia, Salerno, Martina, Schwarze, Frank, Friese, Daniela, Bugert, Joachim J., Brancale, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783601537195442176
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
work_keys_str_mv AT bassettomarcella novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT cimaceciliam novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT bassomattia novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT salernomartina novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT schwarzefrank novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT friesedaniela novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT bugertjoachimj novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections
AT brancaleandrea novelnucleosideanaloguesaseffectiveantiviralagentsforzikavirusinfections