title: Repurposing Kinase Inhibitors as Antiviral Agents to Control Influenza A Virus Replication.
abstract: Influenza A virus (IAV) infection causes seasonal epidemics of contagious respiratory illness that causes substantial morbidity and some mortality. Regular vaccination is the principal strategy for controlling influenza virus, although vaccine efficacy is variable. IAV antiviral drugs are available; however, substantial drug resistance has developed to two of the four currently FDA-approved antiviral drugs. Thus, new therapeutic approaches are being sought to reduce the burden of influenza-related disease. A high-throughput screen using a human kinase inhibitor library was performed targeting an emerging IAV strain (H7N9) in A549 cells. The inhibitor library contained 273 structurally diverse, active cell permeable kinase inhibitors with known bioactivity and safety profiles, many of which are at advanced stages of clinical development. The current study shows that treatment of human A549 cells with kinase inhibitors dinaciclib, flavopiridol, or PIK-75 exhibits potent antiviral activity against H7N9 IAV as well as other IAV strains. Thus, targeting host kinases can provide a broad-spectrum therapeutic approach against IAV. These findings provide a path forward for repurposing existing kinase inhibitors safely as potential antivirals, particularly those that can be tested in vivo and ultimately for clinical use.
authors.affiliation: 1 Department of Infectious Diseases College of Veterinary Medicine, University of Georgia , Athens, Georgia .
authors.forename: Olivia
authors.initials: O
authors.lastname: Perwitasari
authors.affiliation: 1 Department of Infectious Diseases College of Veterinary Medicine, University of Georgia , Athens, Georgia .
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Yan
authors.affiliation: 1 Department of Infectious Diseases College of Veterinary Medicine, University of Georgia , Athens, Georgia .|2 Division of Biological Sciences, University of Georgia , Athens, Georgia .
authors.forename: Jason
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: 1 Department of Infectious Diseases College of Veterinary Medicine, University of Georgia , Athens, Georgia .
authors.forename: Scott
authors.initials: S
authors.lastname: Johnson
authors.affiliation: 1 Department of Infectious Diseases College of Veterinary Medicine, University of Georgia , Athens, Georgia .
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning / Q000379:methods*; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D057166:High-Throughput Screening Assays; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D012449:Safety; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries