A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations

Hutterer C, Eickhoff J, Milbradt J, Korn K, Zeitträger I, Bahsi H, Wagner S, Zischinsky G, Wolf A, Degenhart C, Unger A, Baumann M, Klebl B, Marschall M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Antimicrobial Agents and Chemotherapy American Society for Microbiology

Book Volume: 59

Pages Range: 2062-71

Journal Issue: 4

DOI: 10.1128/AAC.04534-14

Abstract

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.

Authors with CRIS profile

Jens Milbradt
Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Involved external institutions

Lead Discovery Center GmbH DE Germany (DE)

How to cite

APA:

Hutterer, C., Eickhoff, J., Milbradt, J., Korn, K., Zeitträger, I., Bahsi, H.,... Marschall, M. (2015). A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations. Antimicrobial Agents and Chemotherapy, 59(4), 2062-71. https://doi.org/10.1128/AAC.04534-14

MLA:

Hutterer, Corina, et al. "A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations." Antimicrobial Agents and Chemotherapy 59.4 (2015): 2062-71.

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