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Antiviral Res. 2017 Feb;138:61-67. doi: 10.1016/j.antiviral.2016.12.006. Epub 2016 Dec 9.

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

Author information

1
Institute of Infection & Immunity, St George's, University of London, London, UK.
2
MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
3
Department of Infectious Diseases, King's College London, London, UK.
4
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Institute of Infection & Immunity, St George's, University of London, London, UK; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: bstrang@sgul.ac.uk.

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.

KEYWORDS:

Compound; Human cytomegalovirus; IE2; Inhibitor; Kinase; Screen

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