Cyclin‐Dependent Kinases (CDKs) and the Human Cytomegalovirus‐Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations

Wild M, Hahn F, Brückner N, Schütz M, Wangen C, Wagner S, Sommerer M, Strobl S, Marschall M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

International Journal of Molecular Sciences MDPI

Book Volume: 23

Article Number: 2493

Journal Issue: 5

DOI: 10.3390/ijms23052493

Abstract

Human cytomegalovirus (HCMV) is a pathogenic human herpesvirus associated with serious, potentially life‐threatening symptoms in the immunocompromised or immunonaïve host. The limitations encountered by antiviral therapy options currently available include a narrow panel of accessible targets, the induction of viral drug resistance as well as severe drug dosage‐mediated side‐effects. Improved drug‐targeting strategies to resolve these issues are the focus of our investigations. In particular, pharmaceutical kinase inhibitors (PKIs), either directed to host kinases or directed to the viral protein kinase pUL97, have been considered to overcome these restrictions. Recently, we reported the identification of a synergistic combination of two PKIs directed to host cyclin‐dependent kinase 7 (CDK7) and viral CDK ortholog pUL97. Here, we substantiate these findings with the following results: (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV‐infected cells were assessed by confocal imaging, indicating a strong down‐modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF‐UL97 or cellular cyclin knock‐out; (vi) new combinations of HCMV‐specific drug synergy were demonstrated for solely host‐directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti‐HCMV therapy.

Authors with CRIS profile

Markus Wild Institute of Clinical and Molecular Virology Friedrich Hahn Professur für Virologie Martin Schütz Institute of Clinical and Molecular Virology Markus Sommerer Professur für Kinder- und Jugendpsychiatrie und -psychotherapie Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

None - None A088: Regulatory interaction btw. cyclins and cytomegalovirus kinase pUL97: focus on pUL97 drug resistance mutations Feb. 1, 2020 - July 31, 2023

Involved external institutions

4SC AG DE Germany (DE)

How to cite

APA:

Wild, M., Hahn, F., Brückner, N., Schütz, M., Wangen, C., Wagner, S.,... Marschall, M. (2022). Cyclin‐Dependent Kinases (CDKs) and the Human Cytomegalovirus‐Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations. International Journal of Molecular Sciences, 23(5). https://dx.doi.org/10.3390/ijms23052493

MLA:

Wild, Markus, et al. "Cyclin‐Dependent Kinases (CDKs) and the Human Cytomegalovirus‐Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations." International Journal of Molecular Sciences 23.5 (2022).

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