Abstract
Chemogenomic approaches involving highly annotated compound sets and cell based high throughput screening are emerging as a means to identify novel drug targets. We have previously screened a collection of highly characterized kinase inhibitors (Khan et al., Journal of General Virology, 2016) to identify compounds that increase or decrease expression of a human cytomegalovirus (HCMV) protein in infected cells. To identify potential novel anti-HCMV drug targets we used a machine learning approach to relate our phenotypic data from the aforementioned screen to kinase inhibition profiling of compounds used in this screen. Several of the potential targets had no previously reported role in HCMV replication. We focused on one potential anti-HCMV target, MAPK4K, and identified lead compounds inhibiting MAP4K4 that have anti-HCMV activity with little cellular cytotoxicity. We found that treatment of HCMV infected cells with inhibitors of MAP4K4, or an siRNA that inhibited MAP4K4 production, reduced HCMV replication and impaired detection of IE2-60, a viral protein necessary for efficient HCMV replication. Our findings demonstrate the potential of this machine learning approach to identify novel anti-viral drug targets, which can inform the discovery of novel anti-viral lead compounds.
Highlights
Identification of viral and cellular proteins required for virus replication can be a critical step in the discovery of novel anti-viral targets
To identify drug targets from our screening data we revisited our analysis of a screen [33] using the GlaxoSmithKline (GSK) Published Kinase Inhibitor Set (PKIS) [36] and employed a machine learning approach [37] to analyze the relationship between the phenotypic data from our screen and the kinase inhibition profiles of the compounds used in the screen. From this analysis we identified a number of potential drug targets and investigated lead compounds targeting the kinase MAP4K4, whose function in human cytomegalovirus (HCMV) replication was unknown
Further analysis of machine learning resulted in the identification of lead compounds targeting MAP4K4 that had anti-HCMV activity
Summary
Identification of viral and cellular proteins required for virus replication can be a critical step in the discovery of novel anti-viral targets. A number of genetic methods are available to screen infected cells to identify proteins required for virus replication. These include the screening of infected cells using siRNA [1,2,3,4,5,6,7] or CRISPR/Cas9 [8,9,10] and analysis of infected haploid cells. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]. The funders had no role in experimental design, data collection, data interpretation or the decision to submit the work for publication
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