title: Small molecule inhibitors of the c-Jun N-terminal kinase (JNK) possess antiviral activity against highly pathogenic avian and human pandemic influenza A viruses.
abstract: C-Jun N-terminal kinases (JNK) are activated in course of many viral infections. Here we analyzed the activity of JNK inhibitors on influenza A virus (IAV) amplification. Human lung epithelial cells were infected with either the highly pathogenic avian virus strain A/FPV/Bratislava/79 (H7N7) or the pandemic swine-origin influenza virus A/Hamburg/4/09 (H1N1v). The application of the JNK inhibitors SP600125 and AS601245 reduced IAV amplification by suppressing viral protein and RNA synthesis. Although AS601245 appeared to generally block the transcription of newly introduced genes, SP600125 specifically affected viral RNA synthesis. Overexpression of a dominant negative mutant of SEK/MKK4 and siRNA-mediated suppression of JNK2 expression confirmed that specific manipulation of the JNK pathway attenuates virus propagation. An IAV minigenome replication assay revealed that SP600125 did not directly affect the activity of the viral RNA polymerase complex but seems to suppress an anti-influenza nonstructural protein 1-mediated virus supportive function. Finally, when H7N7- or H1N1v-infected mice were treated with SP600125, the viral load is reduced in lungs of treated compared with untreated mice. Our data suggest that this class of ATP competitive inhibitors once optimized for antiviral action potentially represent novel drugs for antiviral intervention.
authors.affiliation: Institute of Molecular Virology, Centre of Molecular Biology of Inflammation, Westfälische Wilhelms University Münster, D-48149 Münster, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Nacken
authors.forename: Christina
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001717:Birds; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D053126:Influenza A Virus, H7N7 Subtype / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000821:virology; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D058873:Pandemics; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017361:Viral Nonstructural Proteins; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D012321:DNA-Directed RNA Polymerases