title: Retinoid derivative Tp80 exhibits anti-hepatitis C virus activity through restoration of GI-GPx expression.
abstract: Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus with an estimated infection in ∼180 million people worldwide, and its chronic infection leads to development of cirrhosis and hepatocellular carcinoma. Although recent development of direct acting antiviral (DAA) compounds improved anti-HCV regimens, alternative therapeutic compounds are still demanded due to an expected emergence of escape mutants for those DAAs. In order to identify novel anti-HCV agents, we conducted chemical library screening for 2086 compounds using HCV Rep-Feo reporter replicon in Huh7 hepatoma cells. Our screening identified retinoid derivative Tp80, which inhibits replication of HCV Rep-Feo (genotype 1b) and JFH1 HCV (genotype 2a) with 0.62 μM and 1.0 μM, respectively, of 50% effective concentration (EC50), at which cytotoxicity is not evident for host hepatocytes. Subsequent transcriptome profiling revealed Tp80 exhibits anti-HCV activity through restoration of gastrointestinal glutathione peroxidase (GI-GPx), suppression of which is responsible for HCV-induced oxidative stress to facilitate HCV replication. Furthermore, comparison of Tp80 with other retinoid derivatives revealed Tp80 shows best potency in both GI-GPx restoration and anti-HCV activity among compounds we examined. In conclusion, our current study provides Tp80 as a promising candidate of anti-HCV compound, suppressing host cellular oxidative stress through a restoration of GI-GPx.
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Biomedical Science PhD Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|Laboratory of Organic and Medicinal Chemistry, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Bao Ngoc
authors.initials: BN
authors.lastname: Nguyen
authors.affiliation: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ajiro
authors.affiliation: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Iida
authors.affiliation: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Denawa
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Hokkaido University Graduate School of Medicine, The Third Department of Internal Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Organic and Medicinal Chemistry, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000821:virology; D002460:Cell Line; D055808:Drug Discovery; D020869:Gene Expression Profiling; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000821:virology; D018384:Oxidative Stress; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D012176:Retinoids; D054852:Small Molecule Libraries; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase
keywords: antiviral agents; hepatitis C virus; microarrays; research and analysis methods; virus classification