title: MEAN inhibits hepatitis C virus replication by interfering with a polypyrimidine tract-binding protein.
abstract: MEAN (6-methoxyethylamino-numonafide) is a small molecule compound, and here, we report that it effectively inhibits hepatitis C virus (HCV) infection in an HCV cell culture system using a JC1-Luc chimeric virus, with a 50% effective concentration (EC50) of 2.36 ± 0.29 μM. Drug combination usage analyses demonstrated that MEAN was synergistic with interferon α, ITX5061 and ribavirin. In addition, MEAN effectively inhibits N415D mutant virus and G451R mutant viral infections. Mechanistic studies show that the treatment of HCV-infected hepatocytes with MEAN inhibits HCV replication but not translation. Furthermore, treatment with MEAN significantly reduces polypyrimidine tract-binding protein (PTB) levels and blocks the cytoplasmic redistribution of PTB upon infection. In the host cytoplasm, PTB is directly associated with HCV replication, and the inhibition of HCV replication by MEAN can result in the sequestration of PTB in treated nuclei. Taken together, these results indicate that MEAN is a potential therapeutic candidate for HCV infection, and the targeting of the nucleo-cytoplasmic translocation of the host PTB protein could be a novel strategy to interrupt HCV replication.
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Xue
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Yanning
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Xiaotang
authors.initials: X
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: State Key Lab of Diagnostic and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, 1st Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D000067556:Internal Ribosome Entry Sites / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010655:Phenylenediamines / Q000494:pharmacology; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012367:RNA, Viral / Q000096:biosynthesis; D012254:Ribavirin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C562029:6-methoxyethylaminonumonafide; D000998:Antiviral Agents; C583499:ITX-5061; D016898:Interferon-alpha; D000067556:Internal Ribosome Entry Sites; D050505:Mutant Proteins; D053644:Naphthalimides; D010655:Phenylenediamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; D013449:Sulfonamides; C485184:enhanced green fluorescent protein; D038941:Polypyrimidine Tract-Binding Protein; D049452:Green Fluorescent Proteins; D012254:Ribavirin
keywords: anti-HCV drug; novel strategy; nucleo-cytoplasmic translocation; polypyrimidine tract-binding protein