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

Yael Wexler-Cohen, Avraham Ashkenazi, Mathias Viard, Robert Blumenthal, Yechiel Shai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4196-4202
Number of pages7
JournalFASEB Journal
Volume24
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteZIABC008303

    Keywords

    • HIV-1 entry inhibitor
    • Membrane fusion
    • Peptide-membrane interaction
    • Viral envelope protein

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