Wild M, Kicuntod J, Seyler L, Wangen C, Bertzbach LD, Conradie AM, Kaufer BB, Wagner S, Michel D, Eickhoff J, Tsogoeva S, Bäuerle T, Hahn F, Marschall M (2021)
Publication Type: Journal article
Publication year: 2021
Book Volume: 22
Pages Range: 1-20
Article Number: 575
Journal Issue: 2
DOI: 10.3390/ijms22020575
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.
APA:
Wild, M., Kicuntod, J., Seyler, L., Wangen, C., Bertzbach, L.D., Conradie, A.M.,... Marschall, M. (2021). Combinatorial drug treatments reveal promising anticytomegaloviral profiles for clinically relevant pharmaceutical kinase inhibitors (PKIs). International Journal of Molecular Sciences, 22(2), 1-20. https://doi.org/10.3390/ijms22020575
MLA:
Wild, Markus, et al. "Combinatorial drug treatments reveal promising anticytomegaloviral profiles for clinically relevant pharmaceutical kinase inhibitors (PKIs)." International Journal of Molecular Sciences 22.2 (2021): 1-20.
BibTeX: Download