Amantadine inhibits hepatitis A virus internal ribosomal entry site-mediated translation in human hepatoma cells.
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.
Kanda
Tatsuo
T
Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan. kandat-cib@umin.ac.jp
Yokosuka
Osamu
O
Imazeki
Fumio
F
Fujiwara
Keiichi
K
Nagao
Keiichi
K
Saisho
Hiromitsu
H
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
D016898:Interferon-alpha; D012315:RNA Caps; D012367:RNA, Viral; D038941:Polypyrimidine Tract-Binding Protein; D000547:Amantadine; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)