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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Cytomegalovirus / drug effects*
  • Cytomegalovirus / physiology
  • DNA Replication / drug effects
  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Immediate-Early Proteins / biosynthesis*
  • Trans-Activators / biosynthesis*
  • Transcription, Genetic / drug effects
  • Viral Proteins / biosynthesis
  • Viral Proteins / genetics
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • IE2 protein, Cytomegalovirus
  • Immediate-Early Proteins
  • Trans-Activators
  • Viral Proteins