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Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins.

Beelontally, R; Wilkie, GS; Lau, B; Goodmaker, CJ; Ho, CMK; Swanson, CM; Deng, X; Wang, J; Gray, NS; Davison, AJ; et al. Beelontally, R; Wilkie, GS; Lau, B; Goodmaker, CJ; Ho, CMK; Swanson, CM; Deng, X; Wang, J; Gray, NS; Davison, AJ; Strang, BL (2017) Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins. Antiviral Res, 138. pp. 61-67. ISSN 1872-9096 https://doi.org/10.1016/j.antiviral.2016.12.006
SGUL Authors: Strang, Blair Lewis

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Abstract

Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production.

Item Type: Article
Additional Information: © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Compound, Human cytomegalovirus, IE2, Inhibitor, Kinase, Screen, Compound, Human cytomegalovirus, IE2, Inhibitor, Kinase, Screen, Virology, 1108 Medical Microbiology, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Antiviral Res
ISSN: 1872-9096
Language: eng
Dates:
DateEvent
1 February 2017Published
9 December 2016Published Online
5 December 2016Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
R01 AI019838NIAID NIH HHSUNSPECIFIED
R01 AI026077NIAID NIH HHSUNSPECIFIED
PubMed ID: 27956134
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/108512
Publisher's version: https://doi.org/10.1016/j.antiviral.2016.12.006

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