title: A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway.
abstract: Identification of novel drug targets and affordable therapeutic agents remains a high priority in the fight against chronic hepatitis C virus (HCV) infection. Here, we report that the cellular proteins prohibitin 1 (PHB1) and 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding step. While predominantly found in mitochondria, PHBs localize to the plasma membrane of hepatocytes through their transmembrane domains and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and inhibited HCV entry at low nanomolar concentrations. A structure-activity analysis of 32 synthetic Roc-A analogs indicated that the chiral, racemic version of aglaroxin C, a natural product biosynthetically related to Roc-A, displayed improved potency and therapeutic index against HCV infection. This study reveals a new class of HCV entry inhibitors that target the PHB1/2-CRaf pathway.
authors: Center for Immunology and Infectious Diseases, Biosciences Division, SRI International, Harrisonburg, VA 22802, USA.
authors: Shufeng
authors: S
authors: Liu
authors: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors: Wenyu
authors: W
authors: Wang
authors: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors: Lauren E
authors: LE
authors: Brown
authors: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, 2901 Caolang Road, Shanghai 201508, China.
authors: Chao
authors: C
authors: Qiu
authors: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors: Neil
authors: N
authors: Lajkiewicz
authors: College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Ting
authors: T
authors: Zhao
authors: Department of Urology, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
authors: Jianhua
authors: J
authors: Zhou
authors: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors: John A
authors: JA
authors: Porco
authors: Center for Immunology and Infectious Diseases, Biosciences Division, SRI International, Harrisonburg, VA 22802, USA.
authors: Tony T
authors: TT
authors: Wang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D000091402:Prohibitins; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; C000717328:PHB protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; C107772:rocaglamide; D019908:Proto-Oncogene Proteins c-raf
keywords: CHIKVpp, HIV particles pseudotyped with Chikungunya virus envelope proteins; Entry factors; Entry inhibitors; HCV; HCV, hepatitis C virus; HCVcc, cell culture grown HCV; HCVpp, lentiviral particles pseudotyped with HCV envelope proteins; MOI, multiplicity of infection; PHB, prohibitin; Rocaglates; VSV-Gpp, HIV particles pseudotyped with vesicular stomatitis virus envelope protein G