Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)

• Main Authors: Markus Wild, Jintawee Kicuntod, Lisa Seyler, Christina Wangen, Luca D. Bertzbach, Andelé M. Conradie, Benedikt B. Kaufer, Sabrina Wagner, Detlef Michel, Jan Eickhoff, Svetlana B. Tsogoeva, Tobias Bäuerle, Friedrich Hahn, Manfred Marschall
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: human cytomegalovirus; antiviral drugs; activity in vitro and in vivo; combinatorial drug analyses; pharmaceutical kinase inhibitors (PKIs); new synergistic combinations
• Online Access: https://www.mdpi.com/1422-0067/22/2/575

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.