title: Amantadine inhibits hepatitis A virus internal ribosomal entry site-mediated translation in human hepatoma cells.
abstract: The effect of six drugs (amantadine, glycyrrhizin, ribavirin, ursodeoxycholic acid, alcohol, and IFN) on HAV RNA translation from the HAV internal ribosomal entry site (IRES) was investigated using a bicistronic reporter construct containing HAV IRES as intragenic spacer. Huh-7 cells and derivatives were transfected with in vitro transcripts, and the reporter gene activity was determined. IFN suppressed both cap-dependent and HAV IRES-dependent translation, while amantadine specifically inhibited HAV IRES-dependent translation. In contrast to IFN, by reporter assay, amantadine did not activate the interferon-stimulated response element (ISRE) or interferon gamma-activated sequence (GAS)-associated pathways. Immunoblot analysis revealed that amantadine had no effect on PKR and on IFN-regulatory factor-1 (IRF-1) expression. These findings demonstrated a novel antiviral effect of amantadine against HAV with or without HCV infection.
authors.affiliation: Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan. kandat-cib@umin.ac.jp
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Fumio
authors.initials: F
authors.lastname: Imazeki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nagao
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Saisho
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D017123:Bacteriophage T7 / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016679:Genome, Viral; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D030041:Hepatitis A virus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects / Q000235:genetics; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013539:Simian virus 40 / Q000235:genetics
chemical_list: D016898:Interferon-alpha; D012315:RNA Caps; D012367:RNA, Viral; D038941:Polypyrimidine Tract-Binding Protein; D000547:Amantadine; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)