A peptide derived from hepatitis C virus E2 envelope protein inhibits a post-binding step in HCV entry.
The HCV envelope proteins E1 and E2 are required for virus binding to cellular receptors and pH-dependent fusion with endosomal membranes. Envelope protein interactions within this multistep process may provide novel targets for development of antiviral agents. To identify E1 and E2 regions involved in critical steps of HCV entry, we screened an E1E2 overlapping peptide library for inhibition of infection using a lentiviral reporter vector pseudotyped with E1E2 envelope proteins. A 16-residue polypeptide containing a portion of the E2 transmembrane domain (Peptide 75) inhibited HCV pseudoparticle infection with an IC50 of approximately 0.3microM and did not inhibit infection by VSV-g pseudoparticles at concentrations up to 50microM. Structure-activity analysis of Peptide 75 showed that antiviral activity was dependent upon L-configuration and hydrophobic character, and that the native sequence was required for maximal activity. Peptide 75 did not show virocidal activity against HCV pseudoparticles or other viruses. Temperature-shift experiments showed that the peptide acted at a post-binding step and that inhibition was further increased when used in combination with an anti-CD81 antibody previously shown to inhibit pseudoparticle entry at a post-binding step. These data suggest that interactions involving the C terminal region of E2 may play an important role in the HCV entry process.
Department of Virology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. jiakechong@aol.com
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Liu
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Tewari
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Kong
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Zhang
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Ingravallo
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Ralston
D000998:Antiviral Agents / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D010455:Peptides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors*; D053586:Virus Internalization
D000998:Antiviral Agents; D010455:Peptides; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus