Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo
| Autor: | Stephan M. Ensminger, S. Abele, Thomas Stamminger, Detlef Michel, William D. Rawlinson, Jodi Anderson, Manfred Marschall, Jan Eickhoff, Mark R. Schleiss, Martina Leis, Yeon Choi, Gillian M. Scott, Bert Klebl, Sabrina Auerochs, Sabine Rechter |
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| Rok vydání: | 2007 |
| Předmět: |
Human cytomegalovirus
Male medicine.drug_class Cell Survival Guinea Pigs Cytomegalovirus Viral Plaque Assay Pharmacology Biology Antiviral Agents Tyrosine-kinase inhibitor Inhibitory Concentration 50 Mice Viral Proteins Gefitinib In vivo Virology medicine Animals Humans Mode of action Protein kinase A Protein Kinase Inhibitors Cells Cultured Sequence Deletion Kinase Phosphotransferases Viral Load medicine.disease In vitro Rats Cytomegalovirus Infections Quinazolines Female medicine.drug |
| Zdroj: | Antiviral research. 79(1) |
| ISSN: | 0166-3542 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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