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

Rooksarr Beelontally, Gavin S. Wilkie, Betty Lau, Charles J. Goodmaker, Catherine M.K. Ho, Chad M. Swanson, Xianming Deng, Jinhua Wang, Nathanael S. Gray, Andrew J. Davison, Blair L. Strang

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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.
Original languageEnglish
Pages (from-to)61-67
Number of pages7
JournalAntiviral Research
Volume138
Early online date9 Dec 2016
DOIs
Publication statusPublished - Feb 2017

Keywords

  • Human cytomegalovirus
  • Screen
  • Kinase
  • Inhibitor
  • Compound
  • IE2

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