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Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo

BACKGROUND: Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of t...

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Autores principales: Hou, Jue, Zhang, Zili, Huang, Qiang, Yan, Jun, Zhang, Xiaohu, Yu, Xiaoliang, Tan, Guihua, Zheng, Chunfu, Xu, Feng, He, Sudan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358049/
https://www.ncbi.nlm.nih.gov/pubmed/28320320
http://dx.doi.org/10.1186/s12879-017-2305-0
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author Hou, Jue
Zhang, Zili
Huang, Qiang
Yan, Jun
Zhang, Xiaohu
Yu, Xiaoliang
Tan, Guihua
Zheng, Chunfu
Xu, Feng
He, Sudan
author_facet Hou, Jue
Zhang, Zili
Huang, Qiang
Yan, Jun
Zhang, Xiaohu
Yu, Xiaoliang
Tan, Guihua
Zheng, Chunfu
Xu, Feng
He, Sudan
author_sort Hou, Jue
collection PubMed
description BACKGROUND: Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of these drugs has led to the emergence of drug-resistant viral strains. Hence, there is an urgent need to develop new anti-HSV agents. METHODS: To identify novel anti-HSV-1 compounds, we screened the LOPAC small scale library of 1280 bioactive compounds to identify inhibitors of HSV-1-induced necroptosis. Further experiments including western blot analysis, Q-PCR analysis and immunohistochemistry were performed to explore the antiviral mechanism of the compounds. RESULTS: Here, we identified PHA767491 as a new inhibitor of HSV. PHA767491 potently blocked the proliferation of HSV in cells, as well as HSV induced cell death. Further, we found that PHA767491 strongly inhibited HSV infection post viral entry. Moreover, PHA767491 reduced the expression of viral genes required for DNA synthesis including UL30/42 DNA polymerase and UL5/8/52 helicase-primase complex. The essential immediate early (IE) genes such as ICP4 and ICP27 are critical for the expression of the early and late genes. Of note, PHA767491 inhibited the expression of all IE genes of both HSV-1 and HSV-2. Importantly, PHA767491 reduced viral titers in the tissues from the mice infected with HSV-1. Consistently, immunohistochemistry analysis showed that PHA767491 dramatically attenuated expression of viral protein gB in the livers. CONCLUSIONS: Taken together, PHA767491 has potent anti-HSV activity by inhibiting viral replication both in vitro and in mouse model. Thus, PHA767491 could be a promising agent for the development of new anti-HSV therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-017-2305-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-53580492017-03-20 Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo Hou, Jue Zhang, Zili Huang, Qiang Yan, Jun Zhang, Xiaohu Yu, Xiaoliang Tan, Guihua Zheng, Chunfu Xu, Feng He, Sudan BMC Infect Dis Research Article BACKGROUND: Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of these drugs has led to the emergence of drug-resistant viral strains. Hence, there is an urgent need to develop new anti-HSV agents. METHODS: To identify novel anti-HSV-1 compounds, we screened the LOPAC small scale library of 1280 bioactive compounds to identify inhibitors of HSV-1-induced necroptosis. Further experiments including western blot analysis, Q-PCR analysis and immunohistochemistry were performed to explore the antiviral mechanism of the compounds. RESULTS: Here, we identified PHA767491 as a new inhibitor of HSV. PHA767491 potently blocked the proliferation of HSV in cells, as well as HSV induced cell death. Further, we found that PHA767491 strongly inhibited HSV infection post viral entry. Moreover, PHA767491 reduced the expression of viral genes required for DNA synthesis including UL30/42 DNA polymerase and UL5/8/52 helicase-primase complex. The essential immediate early (IE) genes such as ICP4 and ICP27 are critical for the expression of the early and late genes. Of note, PHA767491 inhibited the expression of all IE genes of both HSV-1 and HSV-2. Importantly, PHA767491 reduced viral titers in the tissues from the mice infected with HSV-1. Consistently, immunohistochemistry analysis showed that PHA767491 dramatically attenuated expression of viral protein gB in the livers. CONCLUSIONS: Taken together, PHA767491 has potent anti-HSV activity by inhibiting viral replication both in vitro and in mouse model. Thus, PHA767491 could be a promising agent for the development of new anti-HSV therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-017-2305-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-20 /pmc/articles/PMC5358049/ /pubmed/28320320 http://dx.doi.org/10.1186/s12879-017-2305-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Hou, Jue
Zhang, Zili
Huang, Qiang
Yan, Jun
Zhang, Xiaohu
Yu, Xiaoliang
Tan, Guihua
Zheng, Chunfu
Xu, Feng
He, Sudan
Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title_full Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title_fullStr Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title_full_unstemmed Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title_short Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo
title_sort antiviral activity of pha767491 against human herpes simplex virus in vitro and in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358049/
https://www.ncbi.nlm.nih.gov/pubmed/28320320
http://dx.doi.org/10.1186/s12879-017-2305-0
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