Synergistic inhibition of HIV-1 envelope-mediated membrane fusion by inhibitors targeting the N and C-terminal heptad repeats of gp41

J Mol Biol. 2006 Dec 1;364(3):283-9. doi: 10.1016/j.jmb.2006.09.017. Epub 2006 Sep 12.


The human immunodeficiency virus type-1 (HIV-1) envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. Here, we show that N(CCG)-gp41, a class 2 inhibitor, and N36(Mut(e,g)), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudo-typed virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observations for HIV-Env-mediated membrane fusion are discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Drug Synergism
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / metabolism*
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / metabolism*
  • Humans
  • Membrane Fusion*
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Conformation


  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptides