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

Beelontally, R. et al. (2017) Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins. Antiviral Research, 138, pp. 61-67. (doi:10.1016/j.antiviral.2016.12.006) (PMID:27956134) (PMCID:PMC5244968)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilkie, Dr Gavin and Davison, Professor Andrew and Lau, Dr Betty
Authors: Beelontally, R., Wilkie, G. S., Lau, B., Goodmaker, C. J., Ho, C. M.K., Swanson, C. M., Deng, X., Wang, J., Gray, N. S., Davison, A. J., and Strang, B. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antiviral Research
Publisher:Elsevier
ISSN:0166-3542
ISSN (Online):1872-9096
Published Online:09 December 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Antiviral Research 138:61-67
Publisher Policy:Reproduced under a creative commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH