Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo

• Published in: Antiviral research 2008-07, Vol.79 (1), p.49-61
• Main Authors: Schleiss, Mark, Eickhoff, Jan, Auerochs, Sabrina, Leis, Martina, Abele, Silke, Rechter, Sabine, Choi, Yeon, Anderson, Jodi, Scott, Gillian, Rawlinson, William, Michel, Detlef, Ensminger, Stephan, Klebl, Bert, Stamminger, Thomas, Marschall, Manfred
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Cytomegalovirus; Cytomegalovirus - drug effects; Cytomegalovirus - enzymology; Cytomegalovirus - genetics; Cytomegalovirus - physiology; Cytomegalovirus Infections - drug therapy; Cytomegalovirus Infections - physiopathology; Cytomegalovirus Infections - virology; Drug development; Female; Guinea Pigs; Human cytomegalovirus; Humans; Inhibitory Concentration 50; Male; Medical sciences; Mice; Mode of action; Pharmacology. Drug treatments; Phosphotransferases - antagonists & inhibitors; Phosphotransferases - metabolism; Protein kinase inhibitors; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quinazolines - chemistry; Quinazolines - pharmacology; Rats; Sequence Deletion; Viral Load; Viral Plaque Assay; Viral Proteins - antagonists & inhibitors; Viral Proteins - metabolism
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2008.01.154

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 IC 50s 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.