Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 59, Issue 4, Pages 2062-2071Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.04534-14
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Funding
- German Federal Ministry of Education and Research [0313860A, 0315326]
- Max-Planck-Forderstiftung (Munich, Germany)
- Wilhelm Sander-Stiftung [2011.085.1/2]
- Bayerische Forschungsstiftung (Forschungsverbund Biomarker in der Infektionsmedizin)
- Deutsche Forschungsgemeinschaft [SFB796/C3, MA 1289/7-1]
- FFL scholarship (Forderung der Chancengleichheit fur Frauen in Forschung und Lehre, University Erlangen-Nuremberg)
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Protein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle and transcription, both connected with the replication of many viruses. Previously, we developed a CDK7 inhibitor, LDC4297, that inhibits CDK7 in vitro in the nano-picomolar range. Novel data from a kinome-wide evaluation (>330 kinases profiled in vitro) demonstrate a kinase selectivity. Importantly, we provide first evidence for the antiviral potential of the CDK7 inhibitor LDC4297, i.e., in exerting a block of the replication of human cytomegalovirus (HCMV) in primary human fibroblasts at nanomolar concentrations (50% effective concentration, 24.5 +/- 1.3 nM). As a unique feature compared to approved antiherpesviral drugs, inhibition occurred already at the immediate-early level of HCMV gene expression. The mode of antiviral action was considered multifaceted since CDK7-regulated cellular factors that are supportive of HCMV replication were substantially affected by the inhibitors. An effect of LDC4297 was identified in the interference with HCMV-driven inactivation of retinoblastoma protein (Rb), a regulatory step generally considered a hallmark of herpesviral replication. In line with this finding, a broad inhibitory activity of the drug could be demonstrated against a selection of human and animal herpesviruses and adenoviruses, whereas other viruses only showed intermediate drug sensitivity. Summarized, the CDK7 inhibitor LDC4297 is a promising candidate for further antiviral drug development, possibly offering new options for a comprehensive approach to antiviral therapy.
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