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Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5
Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a viru...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Authors. Published by Elsevier B.V.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156294/ https://www.ncbi.nlm.nih.gov/pubmed/30096339 http://dx.doi.org/10.1016/j.antiviral.2018.08.005 |
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author | Wetherill, Laura F. Wasson, Christopher W. Swinscoe, Gemma Kealy, David Foster, Richard Griffin, Stephen Macdonald, Andrew |
author_facet | Wetherill, Laura F. Wasson, Christopher W. Swinscoe, Gemma Kealy, David Foster, Richard Griffin, Stephen Macdonald, Andrew |
author_sort | Wetherill, Laura F. |
collection | PubMed |
description | Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation. |
format | Online Article Text |
id | pubmed-6156294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Authors. Published by Elsevier B.V. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61562942018-10-01 Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 Wetherill, Laura F. Wasson, Christopher W. Swinscoe, Gemma Kealy, David Foster, Richard Griffin, Stephen Macdonald, Andrew Antiviral Res Article Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation. The Authors. Published by Elsevier B.V. 2018-10 2018-08-07 /pmc/articles/PMC6156294/ /pubmed/30096339 http://dx.doi.org/10.1016/j.antiviral.2018.08.005 Text en © 2018 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Wetherill, Laura F. Wasson, Christopher W. Swinscoe, Gemma Kealy, David Foster, Richard Griffin, Stephen Macdonald, Andrew Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title | Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title_full | Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title_fullStr | Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title_full_unstemmed | Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title_short | Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5 |
title_sort | alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (hpv) e5 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156294/ https://www.ncbi.nlm.nih.gov/pubmed/30096339 http://dx.doi.org/10.1016/j.antiviral.2018.08.005 |
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