title: Virus-cell and cell-cell fusion mediated by the HIV-1 envelope glycoprotein is inhibited by short gp41 N-terminal membrane-anchored peptides lacking the critical pocket domain.
abstract: The interactions between the N- and C-terminal heptad repeat (NHR and CHR) regions of the human immunodeficiency virus (HIV-1) glycoprotein gp41 create a structure comprising a 6-helix bundle (SHB). A sequence in the SHB named the "pocket" is crucial for the SHB's stability and for the fusion inhibitory activity of 36-residue NHR peptide N36. We report that a short 27-residue peptide, N27, which lacks the pocket sequence, exhibits potent inhibitory activity in both cell-cell and virus-cell fusion assays when fatty acids were conjugated to its N but not C terminus. Furthermore, mutations in the positions that prevent interaction with the CHR but not with the NHR resulted in a dramatic reduction in N27 activity. These data support a mechanism in which N27 mainly targets the CHR rather than the internal NHR coiled-coil, reveal the N-terminal edge of the endogenous core structure in situ and hence complement our recent findings of the C-terminal edge of the core, and provide a new approach for designing short inhibitors from the NHR region of other lentiviruses due to similarities in their envelope proteins.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Wexler-Cohen
authors.forename: Avraham
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Mathias
authors.initials: M
authors.lastname: Viard
authors.forename: Robert
authors.initials: R
authors.lastname: Blumenthal
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000595:Amino Acid Sequence; D002459:Cell Fusion; D005227:Fatty Acids / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides