Inhibition of HIV-1 envelope glycoprotein-mediated cell fusion by a DL-amino acid-containing fusion peptide: possible recognition of the fusion complex.
The N-terminal fusion peptide (FP) of human immunodeficiency virus-1 (HIV-1) is a potent inhibitor of cell-cell fusion, possibly because of its ability to recognize the corresponding segments inside the fusion complex within the membrane. Here we show that a fusion peptide in which the highly conserved Ile(4), Phe(8), Phe(11), and Ala(14) were replaced by their d-enantiomers (IFFA) is a potent inhibitor of cell-cell fusion. Fourier transform infrared spectroscopy confirmed that despite these drastic modifications, the peptide preserved most of its structure within the membrane. Fluorescence energy transfer studies demonstrated that the diastereomeric peptide interacted with the wild type FP, suggesting this segment as the target site for inhibition of membrane fusion. This is further supported by the similar localization of the wild type and IFFA FPs to microdomains in T cells and the preferred partitioning into ordered regions within sphingomyelin/phosphatidyl-choline/cholesterol giant vesicles. These studies provide insight into the mechanism of molecular recognition within the membrane milieu and may serve in designing novel HIV entry inhibitors.
Gerber
Doron
D
The Weizmann Institute of Science, Rehovot, 76100 Israel.
Pritsker
Moshe
M
Gunther-Ausborn
Susanne
S
Johnson
Benitra
B
Blumenthal
Robert
R
Shai
Yechiel
Y
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism*; D002459:Cell Fusion; D031541:Fluorescence Resonance Energy Transfer; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D013601:T-Lymphocytes / Q000502:physiology; D014759:Viral Envelope Proteins / Q000378:metabolism*
D000596:Amino Acids; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins