title: Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding.
abstract: Hepatitis C virus (HCV) entry is a multiple-step process involving a number of host factors and hence represents a promising target for new antiviral drug development. In search of novel inhibitors of HCV infection, we found that a human apolipoprotein E (apoE) peptide, hEP, containing both a receptor binding fragment and a lipid binding fragment of apoE specifically blocked the entry of cell culture grown HCV (HCVcc) at submicromolar concentrations. hEP caused little cytotoxicity in vitro and remained active even if left 24 hours in cell culture. Interestingly, hEP inhibited neither human immunodeficiency virus (HIV)-HCV pseudotypes (HCVpp) nor HIV and Dengue virus (DENV) infection. Further characterization mapped the anti-HCV activity to a 32-residue region that harbors the receptor binding domain of apoE, but this fragment must contain a cysteine residue at the N-terminus to mediate dimer formation. The anti-HCV activity of the peptide appears to be dependent on both its length and sequence and correlates with its ability to bind lipids. Finally, we demonstrated that the apoE-derived peptides directly blocked the binding of both HCVcc and patient serum-derived virus to hepatoma cells as well as primary human hepatocytes.
  
  
  CONCLUSIONS
  apoE peptides potently inhibit HCV infection and suggest a direct role of apoE in mediating HCV entry. Our findings also highlight the potential of developing apoE mimetic peptides as novel HCV entry inhibitors by targeting HCV-host interactions.
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Liu
authors.forename: Kevin D
authors.initials: KD
authors.lastname: McCormick
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhao
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000138:chemical synthesis / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011973:Receptors, LDL / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001057:Apolipoproteins E; D008081:Liposomes; D010455:Peptides; D011973:Receptors, LDL; D002784:Cholesterol