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Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication

Flaviviruses are relevant animal and human pathogens that include West Nile virus (WNV), Japanese encephalitis virus, dengue virus, or Zika virus, among others. Currently, no licensed therapy is available to fight flaviviral infections. Protein kinases C (PKCs) constitute a family of multifunctional...

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Autores principales: Blázquez, Ana B., Vázquez-Calvo, Ángela, Martín-Acebes, Miguel A., Saiz, Juan-Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850398/
https://www.ncbi.nlm.nih.gov/pubmed/29473907
http://dx.doi.org/10.3390/v10020091
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author Blázquez, Ana B.
Vázquez-Calvo, Ángela
Martín-Acebes, Miguel A.
Saiz, Juan-Carlos
author_facet Blázquez, Ana B.
Vázquez-Calvo, Ángela
Martín-Acebes, Miguel A.
Saiz, Juan-Carlos
author_sort Blázquez, Ana B.
collection PubMed
description Flaviviruses are relevant animal and human pathogens that include West Nile virus (WNV), Japanese encephalitis virus, dengue virus, or Zika virus, among others. Currently, no licensed therapy is available to fight flaviviral infections. Protein kinases C (PKCs) constitute a family of multifunctional lipid-dependent isoenzymes that regulate a wide variety of cellular processes (apoptosis, differentiation, proliferation, cellular transformation, motility, adhesion, etc.) being currently considered at the front line of drug development for the treatment of diverse human disorders. PKCs have also been implicated in different steps during viral replication; however, nowadays, results regarding their role in flavivirus replication are controversial. Here we demonstrate that calphostin C and chelerythrine, two broad-PKC inhibitors that target conventional, novel and atypical PKCs, significantly inhibit WNV multiplication in cell culture without affecting cell viability. A reduction of viral yields was observed in treated cells when compared with mock-treated cells. Likewise, immunofluorescence detection of viral enveloped E protein was reduced in treated cells, as was the amount of viral RNA released to the supernatant, mainly in those treated with chelerythrine. On the other hand, two PKC inhibitors specific for conventional and novel isoforms (staurosporine and enzastaurine) did not show any significant effect in WNV multiplication. These results suggested that PKCs, more probably atypical PKCs, are likely involved in WNV multiplication, although both broad-spectrum tested drugs seem to act through different mechanisms, and point to them as potential antiviral candidates for WNV, as well as for other related flaviviruses.
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spelling pubmed-58503982018-03-16 Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication Blázquez, Ana B. Vázquez-Calvo, Ángela Martín-Acebes, Miguel A. Saiz, Juan-Carlos Viruses Article Flaviviruses are relevant animal and human pathogens that include West Nile virus (WNV), Japanese encephalitis virus, dengue virus, or Zika virus, among others. Currently, no licensed therapy is available to fight flaviviral infections. Protein kinases C (PKCs) constitute a family of multifunctional lipid-dependent isoenzymes that regulate a wide variety of cellular processes (apoptosis, differentiation, proliferation, cellular transformation, motility, adhesion, etc.) being currently considered at the front line of drug development for the treatment of diverse human disorders. PKCs have also been implicated in different steps during viral replication; however, nowadays, results regarding their role in flavivirus replication are controversial. Here we demonstrate that calphostin C and chelerythrine, two broad-PKC inhibitors that target conventional, novel and atypical PKCs, significantly inhibit WNV multiplication in cell culture without affecting cell viability. A reduction of viral yields was observed in treated cells when compared with mock-treated cells. Likewise, immunofluorescence detection of viral enveloped E protein was reduced in treated cells, as was the amount of viral RNA released to the supernatant, mainly in those treated with chelerythrine. On the other hand, two PKC inhibitors specific for conventional and novel isoforms (staurosporine and enzastaurine) did not show any significant effect in WNV multiplication. These results suggested that PKCs, more probably atypical PKCs, are likely involved in WNV multiplication, although both broad-spectrum tested drugs seem to act through different mechanisms, and point to them as potential antiviral candidates for WNV, as well as for other related flaviviruses. MDPI 2018-02-23 /pmc/articles/PMC5850398/ /pubmed/29473907 http://dx.doi.org/10.3390/v10020091 Text en © 2018 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
Blázquez, Ana B.
Vázquez-Calvo, Ángela
Martín-Acebes, Miguel A.
Saiz, Juan-Carlos
Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title_full Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title_fullStr Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title_full_unstemmed Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title_short Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication
title_sort pharmacological inhibition of protein kinase c reduces west nile virus replication
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850398/
https://www.ncbi.nlm.nih.gov/pubmed/29473907
http://dx.doi.org/10.3390/v10020091
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