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Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways
Influenza A viruses (IAV) can cause severe global pandemic outbreaks. The currently licensed antiviral drugs are not very effective and prone to viral resistance. Thus, novel effective and broadly active drugs are urgently needed. We have identified the cellular Raf/MEK/ERK signaling cascade as cruc...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735105/ https://www.ncbi.nlm.nih.gov/pubmed/29312159 http://dx.doi.org/10.3389/fmicb.2017.02426 |
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author | Holzberg, Magdalena Boergeling, Yvonne Schräder, Tobias Ludwig, Stephan Ehrhardt, Christina |
author_facet | Holzberg, Magdalena Boergeling, Yvonne Schräder, Tobias Ludwig, Stephan Ehrhardt, Christina |
author_sort | Holzberg, Magdalena |
collection | PubMed |
description | Influenza A viruses (IAV) can cause severe global pandemic outbreaks. The currently licensed antiviral drugs are not very effective and prone to viral resistance. Thus, novel effective and broadly active drugs are urgently needed. We have identified the cellular Raf/MEK/ERK signaling cascade as crucial for IAV replication and suitable target for an antiviral intervention. Since this signaling cascade is aberrantly activated in many human cancers, several clinically approved inhibitors of Raf and MEK are now available. Here we explored the anti-IAV action of the licensed B-Raf(V600E) inhibitor Vemurafenib. Treatment of B-Raf(WT) cells with Vemurafenib induced a hyperactivation of the Raf/MEK/ERK cascade rather than inhibiting its activation upon IAV infection. Despite this hyperactivation, which has also been confirmed by others, Vemurafenib still strongly limited IAV-induced activation of other signaling cascades especially of p38 and JNK mitogen-activated protein kinase (MAPK) pathways. Most interestingly, Vemurafenib inhibited virus-induced apoptosis via impaired expression of apoptosis-inducing cytokines and led to hampered viral protein expression most likely due to the decreased activation of p38 and JNK MAPK. These multiple actions resulted in a profound and broadly active inhibition of viral replication, up to a titer reduction of three orders of a magnitude. Thus, while Vemurafenib did not act similar to MEK inhibitors, it displays strong antiviral properties via a distinct and multi-target mode of action. |
format | Online Article Text |
id | pubmed-5735105 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57351052018-01-08 Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways Holzberg, Magdalena Boergeling, Yvonne Schräder, Tobias Ludwig, Stephan Ehrhardt, Christina Front Microbiol Microbiology Influenza A viruses (IAV) can cause severe global pandemic outbreaks. The currently licensed antiviral drugs are not very effective and prone to viral resistance. Thus, novel effective and broadly active drugs are urgently needed. We have identified the cellular Raf/MEK/ERK signaling cascade as crucial for IAV replication and suitable target for an antiviral intervention. Since this signaling cascade is aberrantly activated in many human cancers, several clinically approved inhibitors of Raf and MEK are now available. Here we explored the anti-IAV action of the licensed B-Raf(V600E) inhibitor Vemurafenib. Treatment of B-Raf(WT) cells with Vemurafenib induced a hyperactivation of the Raf/MEK/ERK cascade rather than inhibiting its activation upon IAV infection. Despite this hyperactivation, which has also been confirmed by others, Vemurafenib still strongly limited IAV-induced activation of other signaling cascades especially of p38 and JNK mitogen-activated protein kinase (MAPK) pathways. Most interestingly, Vemurafenib inhibited virus-induced apoptosis via impaired expression of apoptosis-inducing cytokines and led to hampered viral protein expression most likely due to the decreased activation of p38 and JNK MAPK. These multiple actions resulted in a profound and broadly active inhibition of viral replication, up to a titer reduction of three orders of a magnitude. Thus, while Vemurafenib did not act similar to MEK inhibitors, it displays strong antiviral properties via a distinct and multi-target mode of action. Frontiers Media S.A. 2017-12-14 /pmc/articles/PMC5735105/ /pubmed/29312159 http://dx.doi.org/10.3389/fmicb.2017.02426 Text en Copyright © 2017 Holzberg, Boergeling, Schräder, Ludwig and Ehrhardt. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Holzberg, Magdalena Boergeling, Yvonne Schräder, Tobias Ludwig, Stephan Ehrhardt, Christina Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title | Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title_full | Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title_fullStr | Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title_full_unstemmed | Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title_short | Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways |
title_sort | vemurafenib limits influenza a virus propagation by targeting multiple signaling pathways |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735105/ https://www.ncbi.nlm.nih.gov/pubmed/29312159 http://dx.doi.org/10.3389/fmicb.2017.02426 |
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