Cytomegalovirus infection is associated with severe disease in immunocompromised individuals. Current antiviral therapy faces several limitations. In a search of novel drug candidates, we describe here the anti-cytomegaloviral properties of two compounds of the chemical class of quinazolines, gefitinib (Iressa®) and Ax7396 (RGB-315389). Both compounds showed strong inhibitory effects in vitro against human and animal cytomegaloviruses with IC50s in a low micromolar range. Cytotoxicity did not occur at these effective concentrations. The antiviral mode of action was based on the inhibition of protein kinase activity, mainly directed to a viral target kinase (UL97/M97) in addition to cellular target candidates. This was demonstrated by a high sensitivity of the respective protein kinases in vitro and by infection experiments with viral mutants carrying genomic alterations in the ORF UL97/M97 modulating viral drug sensitivity. In a guinea pig model, gefitinib showed inhibition of cytomegaloviral loads in blood and lung tissue. Importantly, the rate of mortality of infected animals was reduced by gefitinib treatment. In contrast to the in vitro data, Ax7396 showed no significant antiviral activity in a mouse model. Further in vivo analyses have to assess the potential use of gefitinib in the treatment of cytomegalovirus disease.
Bibliographical noteFunding Information:
We thank Michael McVoy and Xiaohong Cui (Department Pediatrics, Virginia Univ., Richmond, VA) for providing important materials, Michael Mach, Florian Weisel and cooperators (University Erlangen-Nuremberg) for support in animal experiments, Lars Dölken and Ulrich Koszinowski (Max von Pettenkofer-Institute, University Munich, Germany) for providing MCMV mutants and Stipan Jonjic (Department of Histology and Embryology), University Rijeka, Croatia for providing MAb CROMA 101. The following reagents were obtained from the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: 759rD100, GDGrXbaF4 and GDGrP53 (contributor Dr. D. Coen). The study was supported by the Bayerische Forschungsstiftung (grant 576/03), Deutsche Forschungsgemeinschaft (grant Ma 1289/4-1) and Interdisciplinary Center of Clinical Research of the University Erlangen-Nuremberg (IZKF grant A13).
- Animal models
- Antiviral activity
- Drug development
- Human cytomegalovirus
- Mode of action
- Protein kinase inhibitors