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

• Published in: The FASEB journal Vol. 24; no. 11; pp. 4196 - 4202
• Main Authors: Wexler-Cohen, Yael, Ashkenazi, Avraham, Viard, Mathias, Blumenthal, Robert, Shai, Yechiel
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.11.2010
• Subjects: Amino Acid Sequence; Cell Fusion; Fatty Acids - chemistry; HIV Envelope Protein gp41 - genetics; HIV Envelope Protein gp41 - metabolism; HIV Fusion Inhibitors - pharmacology; HIV-1 - metabolism; Humans; Jurkat Cells; Molecular Sequence Data; Peptides - pharmacology; Protein Binding - drug effects; Protein Structure, Tertiary; Virus Internalization - drug effects
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-151704

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.--Wexler-Cohen, Y., Ashkenazi, A., Viard, M., Blumenthal, R., Shai, Y. 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.