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High Throughput Screening of a GlaxoSmithKline Protein Kinase Inhibitor Set Identifies an Inhibitor of Human Cytomegalovirus Replication that Prevents CREB and Histone H3 Post-Translational Modification.

Khan, AS; Murray, MJ; Ho, CMK; Zuercher, WJ; Reeves, MB; Strang, BL (2017) High Throughput Screening of a GlaxoSmithKline Protein Kinase Inhibitor Set Identifies an Inhibitor of Human Cytomegalovirus Replication that Prevents CREB and Histone H3 Post-Translational Modification. J Gen Virol, 98. pp. 754-768. ISSN 1465-2099 https://doi.org/10.1099/jgv.0.000713
SGUL Authors: Strang, Blair Lewis

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Abstract

To identify new compounds with anti-human cytomegalovirus (HCMV) activity and new anti-HCMV targets, we developed a high throughput strategy to screen a GlaxoSmithKline (GSK) Published Kinase Inhibitor Set (PKIS). This collection contains a range of extensively characterized compounds grouped into chemical families (chemotypes). From our screen we identified compounds within chemotypes that impede HCMV replication and identified kinase proteins associated with inhibition of HCMV replication that are potential novel anti-HCMV targets. We focused our study on a top "hit" in our screen, SB-734117, which we found inhibits productive replication of several HCMV strains. Kinase selectivity data indicated that SB-734117 exhibits polypharmacology and is an inhibitor of several proteins from the AGC and CMCG kinase groups. Using western blotting we found that SB-734711 inhibited accumulation of HCMV immediate-early proteins, phosphorylation of cellular proteins involved in immediate-early protein production (CREB and histone H3) and histone H3 lysine 36 trimethylation (H3K36me3). Therefore, we identify SB-734117 as a novel anti-HCMV compound and find that inhibition of AGC and CMCG kinase proteins during productive HCMV replication is associated with inhibition of viral protein production and prevents post-translational modification of cellular factors associated with viral protein production.

Item Type: Article
Additional Information: © 2017 Microbiology Society. Version of record available online at http://dx.doi.org/10.1099/jgv.0.000713
Keywords: Virology, 06 Biological Sciences, 07 Agricultural And Veterinary Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: J Gen Virol
ISSN: 1465-2099
Language: eng
Dates:
DateEvent
1 April 2017Published
18 January 2017Published Online
16 January 2017Accepted
Publisher License: Publisher's own licence
PubMed ID: 28100301
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108546
Publisher's version: https://doi.org/10.1099/jgv.0.000713

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