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.

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 die "pocket" is crucial for die SHB's stability and for die fusion inhibitory activity of 36-residue NHR peptide N36. We report that a short 27-residue peptide, N27, which lacks die 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 die CHR but not with the NHR resulted in a dramatic reduction in N27 activity. These data support a mechanism in which N27 mainly targets die CHR rather than die internal NHR coiled-coil, reveal the N-terminal edge of die endogenous core structure in situ and hence complement our recent findings of die C-terminal edge of die core, and provide a new approach for designing short inhibitors from die NHR region of other lentiviruses due to similarities in their envelope proteins. [ABSTRACT FROM AUTHOR]