title: Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins.
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.
authors.affiliation: Institute of Infection & Immunity, St George's, University of London, London, UK.
authors.forename: Rooksarr
authors.initials: R
authors.lastname: Beelontally
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Wilkie
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Betty
authors.initials: B
authors.lastname: Lau
authors.affiliation: Institute of Infection & Immunity, St George's, University of London, London, UK.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Goodmaker
authors.affiliation: Institute of Infection & Immunity, St George's, University of London, London, UK.
authors.forename: Catherine M K
authors.initials: CMK
authors.lastname: Ho
authors.affiliation: Department of Infectious Diseases, King's College London, London, UK.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Swanson
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davison
authors.affiliation: 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.
authors.forename: Blair L
authors.initials: BL
authors.lastname: Strang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D015534:Trans-Activators / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D014764:Viral Proteins
keywords: Compound; Human cytomegalovirus; IE2; Inhibitor; Kinase; Screen