title: Selective estrogen receptor modulators inhibit hepatitis C virus infection at multiple steps of the virus life cycle.
abstract: We screened for hepatitis C virus (HCV) inhibitors using the JFH-1 viral culture system and found that selective estrogen receptor modulators (SERMs), such as tamoxifen, clomifene, raloxifene, and other estrogen receptor α (ERα) antagonists, inhibited HCV infection. Treatment with SERMs for the first 2 h and treatment 2-24 h after viral inoculation reduced the production of HCV RNA. Treating persistently JFH-1 infected cells with SERMs resulted in a preferential inhibition of extracellular HCV RNA compared to intracellular HCV RNA. When we treated two subgenomic replicon cells, which harbor HCV genome genotype 2a (JFH-1) or genotype 1b, SERMs reduced HCV genome copies and viral protein NS5A. SERMs inhibited the entry of HCV pseudo-particle (HCVpp) genotypes 1a, 1b, 2a, 2b and 4 but did not inhibit vesicular stomatitis virus (VSV) entry. Further experiment using HCVpp indicated that tamoxifen affected both viral binding to cell and post-binding events including endocytosis. Taken together, SERMs seemed to target multiple steps of HCV viral life cycle: attachment, entry, replication, and post replication events. SERMs may be potential candidates for the treatment of HCV infection.
authors.affiliation: Department of Bioactive Molecules, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. murakami@nih.go.jp
authors.forename: Yuko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukasawa
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Hidesuke
authors.initials: H
authors.lastname: Fukazawa
mesh_terms: D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018406:Virus Physiological Phenomena / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D012333:RNA, Messenger; D012367:RNA, Viral; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase