title: Identification of a novel drug lead that inhibits HCV infection and cell-to-cell transmission by targeting the HCV E2 glycoprotein.
abstract: Hepatitis C Virus (HCV) infects 200 million individuals worldwide. Although several FDA approved drugs targeting the HCV serine protease and polymerase have shown promising results, there is a need for better drugs that are effective in treating a broader range of HCV genotypes and subtypes without being used in combination with interferon and/or ribavirin. Recently, two crystal structures of the core of the HCV E2 protein (E2c) have been determined, providing structural information that can now be used to target the E2 protein and develop drugs that disrupt the early stages of HCV infection by blocking E2's interaction with different host factors. Using the E2c structure as a template, we have created a structural model of the E2 protein core (residues 421-645) that contains the three amino acid segments that are not present in either structure. Computational docking of a diverse library of 1,715 small molecules to this model led to the identification of a set of 34 ligands predicted to bind near conserved amino acid residues involved in the HCV E2: CD81 interaction. Surface plasmon resonance detection was used to screen the ligand set for binding to recombinant E2 protein, and the best binders were subsequently tested to identify compounds that inhibit the infection of Huh-7 cells by HCV. One compound, 281816, blocked E2 binding to CD81 and inhibited HCV infection in a genotype-independent manner with IC50's ranging from 2.2 µM to 4.6 µM. 281816 blocked the early and late steps of cell-free HCV entry and also abrogated the cell-to-cell transmission of HCV. Collectively the results obtained with this new structural model of E2c suggest the development of small molecule inhibitors such as 281816 that target E2 and disrupt its interaction with CD81 may provide a new paradigm for HCV treatment.
authors.affiliation: Department of Chemistry, The American University in Cairo, New Cairo, Egypt.
authors.forename: Reem R
authors.initials: RR
authors.lastname: Al Olaby
authors.affiliation: Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cocquerel
authors.affiliation: Pathogen Bioinformatics, Lawrence Livermore National Laboratory, Livermore, CA, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Zemla
authors.affiliation: Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Saas
authors.affiliation: Center for Infection and Immunity of Lille, CNRS-UMR8204/Inserm-U1019, Pasteur Institute of Lille, University of Lille North of France, Lille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.affiliation: Protein Expression Center, Beckman Institute, California Institute of Technology, Pasadena, CA, United States of America.
authors.forename: Jost
authors.initials: J
authors.lastname: Vielmetter
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marcotrigiano
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, United States of America.
authors.forename: Abdul Ghafoor
authors.initials: AG
authors.lastname: Khan
authors.affiliation: Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America.
authors.forename: Felipe
authors.initials: F
authors.lastname: Vences Catalan
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Perryman
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Center for Emerging & Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America; Department of Pharmacology and Physiology, Rutgers University-New Jersey Medical School, Newark, NJ, United States of America.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, United States of America.
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.affiliation: Department of Medicine, Stanford University Medical Center, Stanford, CA, United States of America.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Levy
authors.affiliation: Department of Applied Science, University of California Davis, Davis, CA, United States of America.
authors.forename: Rod
authors.initials: R
authors.lastname: Balhorn
authors.affiliation: Department of Chemistry, The American University in Cairo, New Cairo, Egypt.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Azzazy
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D040681:Structural Homology, Protein; D020349:Surface Plasmon Resonance; D060225:Tetraspanin 28 / Q000378:metabolism; D013816:Thermodynamics; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D011994:Recombinant Proteins; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus