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- Title
Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs).
- Authors
Wild, Markus; Kicuntod, Jintawee; Seyler, Lisa; Wangen, Christina; Bertzbach, Luca D.; Conradie, Andelé M.; Kaufer, Benedikt B.; Wagner, Sabrina; Michel, Detlef; Eickhoff, Jan; Tsogoeva, Svetlana B.; Bäuerle, Tobias; Hahn, Friedrich; Marschall, Manfred
- Abstract
Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs' antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.
- Subjects
CYTOMEGALOVIRUSES; KINASE inhibitors; CYCLIN-dependent kinases; HUMAN cytomegalovirus; ANTINEOPLASTIC agents; DRUG interactions; ANTIVIRAL agents
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 2, p575
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22020575