Publikationsdatenbank

Combinatorial drug treatments reveal promising anticytomegaloviral profiles for clinically relevant pharmaceutical kinase inhibitors (PKIs) (2021)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Wild, Markus

Kicuntod, Jintawee

Seyler, Lisa

Wangen, Christina

Bertzbach, Luca D. (WE 5)

Conradie, Andelé M. (WE 5)

Kaufer, Benedikt B. (WE 5)

Wagner, Sabrina

Michel, Detlef

Eickhoff, Jan

Tsogoeva, Svetlana B.

Bäuerle, Tobias

Hahn, Friedrich

Marschall, Manfred

Quelle

International journal of molecular sciences

Bandzählung: 22

Heftzählung: 2

Seiten: Artikel 575

ISSN: 1422-0067

Sprache

Englisch

Verweise

URL (Volltext): https://www.mdpi.com/1422-0067/22/2/575

DOI: 10.3390/ijms22020575

Pubmed: 33430060

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.