title: Receptor tyrosine kinase inhibitors that block replication of influenza a and other viruses.
abstract: We have previously reported that two receptor tyrosine kinase inhibitors (RTKIs), called AG879 and tyrphostin A9 (A9), can each block the replication of influenza A virus in cultured cells. In this study, we further characterized the in vitro antiviral efficacies and specificities of these agents. The 50% effective concentration (EC(50)) of each against influenza A was found to be in the high nanomolar range, and the selectivity index (SI = 50% cytotoxic concentration [CC(50)]/EC(50)) was determined to be >324 for AG879 and 50 for A9, indicating that therapeutically useful concentrations of each drug produce only low levels of cytotoxicity. Each compound showed efficacy against representative laboratory strains of both human influenza A (H1N1 or H3N2) and influenza B viruses. Importantly, no drug-resistant influenza virus strains emerged even after 25 viral passages in the presence of AG879, whereas viruses resistant to amantadine appeared after only 3 passages. AG879 and A9 each also exhibited potent inhibitory activity against a variety of other RNA and DNA viruses, including Sendai virus (Paramyxoviridae), herpes simplex virus (Herpesviridae), mouse hepatitis virus (Coronaviridae), and rhesus rotavirus (Reoviridae), but not against Pichinde virus (Arenaviridae). These results together suggest that RTKIs may be useful as therapeutics against viral pathogens, including but not limited to influenza, due to their high selectivity indices, low frequency of drug resistance, and broad-spectrum antiviral activities.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.forename: Nishi R
authors.initials: NR
authors.lastname: Sharma
authors.forename: Hinh
authors.initials: H
authors.lastname: Ly
authors.forename: Tristram G
authors.initials: TG
authors.lastname: Parslow
authors.forename: Yuying
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002642:Chick Embryo; D006224:Cricetinae; D004267:DNA Viruses / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000401:mortality / Q000821:virology; D012328:RNA Viruses / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D020032:Tyrphostins; C406122:tyrphostin A9; D020794:Receptor Protein-Tyrosine Kinases