title: Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo.
abstract: 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(50)s 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.
authors.affiliation: Center for Infectious Diseases and Microbiology Translational Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Schleiss
authors.forename: Jan
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Sabrina
authors.initials: S
authors.lastname: Auerochs
authors.forename: Martina
authors.initials: M
authors.lastname: Leis
authors.forename: Silke
authors.initials: S
authors.lastname: Abele
authors.forename: Sabine
authors.initials: S
authors.lastname: Rechter
authors.forename: Yeon
authors.initials: Y
authors.lastname: Choi
authors.forename: Jodi
authors.initials: J
authors.lastname: Anderson
authors.forename: Gillian
authors.initials: G
authors.lastname: Scott
authors.forename: William
authors.initials: W
authors.lastname: Rawlinson
authors.forename: Detlef
authors.initials: D
authors.lastname: Michel
authors.forename: Stephan
authors.initials: S
authors.lastname: Ensminger
authors.forename: Bert
authors.initials: B
authors.lastname: Klebl
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017384:Sequence Deletion; D019562:Viral Load; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014764:Viral Proteins; D010770:Phosphotransferases