title: Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity.
abstract: Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti-herpesviral strategies.
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany. Electronic address: corina.hutterer@viro.med.uni-erlangen.de.
authors.forename: Corina
authors.initials: C
authors.lastname: Hutterer
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
authors.affiliation: Serology and Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick NSW 2013 and SOMS and BABS, University of NSW, Sydney, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: 4SC Discovery GmbH, Martinsried, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Zaja
authors.affiliation: 4SC Discovery GmbH, Martinsried, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.affiliation: 4SC Discovery GmbH, Martinsried, Germany.
authors.forename: Christophe
authors.initials: C
authors.lastname: Henry
authors.affiliation: 4SC Discovery GmbH, Martinsried, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Steingruber
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Sonntag
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zeitträger
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Hanife
authors.initials: H
authors.lastname: Bahsi
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.affiliation: Serology and Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick NSW 2013 and SOMS and BABS, University of NSW, Sydney, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Rawlinson
authors.affiliation: 4SC Discovery GmbH, Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strobl
authors.affiliation: Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Germany. Electronic address: manfred.marschall@viro.med.uni-erlangen.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects; D016503:Drug Delivery Systems; D055808:Drug Discovery; D005347:Fibroblasts / Q000821:virology; D015774:Ganciclovir / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D006247:Harmine / Q000037:antagonists & inhibitors; D006564:Herpesviridae / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta / Q000821:virology; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000235:genetics; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D000097603:Dyrk Kinases
chemical_list: D000998:Antiviral Agents; D015774:Ganciclovir; D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: Antiviral drug target; Antiviral therapy; Broad anti-herpesviral activity; DYRK inhibitors; Human cytomegalovirus; Virus-induced upregulation of DYRK1A and DYRK1B