Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers.

Wild M, Karner D, Eickhoff J, Wagner S, Kicuntod J, Chang W, Barry P, Jonjić S, Lenac Roviš T, Marschall M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Pharmaceutics MDPI

Book Volume: 15

Journal Issue: 12

DOI: 10.3390/pharmaceutics15122680

Abstract

Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.

Authors with CRIS profile

Markus Wild Institute of Clinical and Molecular Virology Jintawee Kicuntod Institute of Clinical and Molecular Virology Manfred Marschall Medizinische Fakultät

Involved external institutions

Lead Discovery Center GmbH DE Germany (DE) University of California Davis (UCDAVIS) US United States (USA) (US) Sveučilište u Rijeci / University of Rijeka HR Croatia (HR)

How to cite

APA:

Wild, M., Karner, D., Eickhoff, J., Wagner, S., Kicuntod, J., Chang, W.,... Marschall, M. (2023). Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers. Pharmaceutics, 15(12). https://doi.org/10.3390/pharmaceutics15122680

MLA:

Wild, Markus, et al. "Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers." Pharmaceutics 15.12 (2023).

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