A synthetic all D-amino acid peptide corresponding to the N-terminal sequence of HIV-1 gp41 recognizes the wild-type fusion peptide in the membrane and inhibits HIV-1 envelope glycoprotein-mediated cell fusion.
Recent studies demonstrated that a synthetic fusion peptide of HIV-1 self-associates in phospholipid membranes and inhibits HIV-1 envelope glycoprotein-mediated cell fusion, presumably by interacting with the N-terminal domain of gp41 and forming inactive heteroaggregates [Kliger, Y., Aharoni, A., Rapaport, D., Jones, P., Blumenthal, R. & Shai, Y. (1997) J. Biol. Chem. 272, 13496-13505]. Here, we show that a synthetic all D-amino acid peptide corresponding to the N-terminal sequence of HIV-1 gp41 (D-WT) of HIV-1 associates with its enantiomeric wild-type fusion (WT) peptide in the membrane and inhibits cell fusion mediated by the HIV-1 envelope glycoprotein. D-WT does not inhibit cell fusion mediated by the HIV-2 envelope glycoprotein. WT and D-WT are equally potent in inducing membrane fusion. D-WT peptide but not WT peptide is resistant to proteolytic digestion. Structural analysis showed that the CD spectra of D-WT in trifluoroethanol/water is a mirror image of that of WT, and attenuated total reflectance-fourier transform infrared spectroscopy revealed similar structures and orientation for the two enantiomers in the membrane. The results reveal that the chirality of the synthetic peptide corresponding to the HIV-1 gp41 N-terminal sequence does not play a role in liposome fusion and that the peptides' chirality is not necessarily required for peptide-peptide interaction within the membrane environment. Furthermore, studies along these lines may provide criteria to design protease-resistant therapeutic agents against HIV and other viruses.
Pritsker
M
M
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel.
Jones
P
P
Blumenthal
R
R
Shai
Y
Y
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002942:Circular Dichroism; D015686:Gene Products, env / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010715:Phosphatidylglycerols / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015686:Gene Products, env; D015700:HIV Envelope Protein gp41; D008051:Lipid Bilayers; D008081:Liposomes; D010446:Peptide Fragments; D010715:Phosphatidylglycerols; D011993:Recombinant Fusion Proteins; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol