title: The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors.
abstract: HCMV is a member of the family Herpesviridae and represents a worldwide distributed pathogen with seropositivity rates in the adult population ranging between 40% and 90%. Notably, HCMV infection is a serious, sometimes life-threatening medical problem for newborns and immunosuppressed individuals, including transplant recipients and patients under antitumoral chemotherapy. Current standard therapy with valganciclovir has the disadvantage of inducing drug-resistant virus mutants and toxicity-related side effects. Our analysis stresses the earlier finding that kinase inhibitors of the quinazoline class exert an antiviral response by targeting the viral protein kinase pUL97 without inducing resistance. Therefore, quinazolines have been used as a core structure to gain insight in the mode of inhibitor-kinase interaction. Here, we demonstrate that (i) the novel quinazolines Vi7392 and Vi7453 are highly active against HCMV laboratory and clinically relevant strains including maribavir- and ganciclovir-resistant variants, (ii) antiviral activity is not cell-type specific and was also detected in a placental explant tissue model using a genetically intact HCMV strain (iii) the viral kinase pUL97 represents a target of the anticytomegaloviral activity of these compounds, (iv) induction of pUL97-conferring drug resistance was not detectable under single-step selection, thus differed from the induction of ganciclovir resistance, and (v) pUL97 drug docking simulations enabled detailed insights into specific drug-target binding properties providing a promising basis for the design of optimized kinase inhibitors. These novel findings may open new prospects for the future medical use of quinazoline drug candidates and the use of drug-target dynamic simulations for rational design of antivirals.
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany. Electronic address: corina.hutterer@viro.med.uni-erlangen.de.
authors: C
authors: C
authors: Hutterer
authors: Serology and Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick NSW 2013 and SOMS and BABS, University of NSW, Sydney, Australia.
authors: S
authors: S
authors: Hamilton
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
authors: M
authors: M
authors: Steingruber
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
authors: I
authors: I
authors: Zeitträger
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
authors: H
authors: H
authors: Bahsi
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
authors: N
authors: N
authors: Thuma
authors: Serology and Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick NSW 2013 and SOMS and BABS, University of NSW, Sydney, Australia.
authors: Z
authors: Z
authors: Naing
authors: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
authors: Z
authors: Z
authors: Örfi
authors: Semmelweis University, Department of Pharmaceutical Chemistry, Budapest, Hungary.
authors: L
authors: L
authors: Örfi
authors: Division of Bioinformatics, Institute of Biochemistry, FAU of Erlangen-Nürnberg, Erlangen, Germany.
authors: E
authors: E
authors: Socher
authors: Division of Bioinformatics, Institute of Biochemistry, FAU of Erlangen-Nürnberg, Erlangen, Germany.
authors: H
authors: H
authors: Sticht
authors: Serology and Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick NSW 2013 and SOMS and BABS, University of NSW, Sydney, Australia.
authors: W
authors: W
authors: Rawlinson
authors: Division of Infectious Diseases, Oregon Health and Science University and VA Medical Center, Portland, USA.
authors: S
authors: S
authors: Chou
authors: Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
authors: V J
authors: VJ
authors: Haupt
authors: Institute of Clinical and Molecular Virology, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
authors: M
authors: M
authors: Marschall
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D015195:Drug Design; D024882:Drug Resistance, Viral; D005260:Female; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D014764:Viral Proteins / Q000737:chemistry / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014764:Viral Proteins; C000624355:pUL97 protein, cytomegalovirus
keywords: Antiviral drug target; Homology model of pUL97; Human cytomegalovirus; Quinazoline compounds; Viral kinase pUL97; pUL97 drug docking simulation