The LLSGIV stretch of the N-terminal region of HIV-1 gp41 is critical for binding to a model peptide, T20.
A number of peptides and peptide analogs derived from the membrane proximal region of gp41 ectodomain are found to be effective inhibitors of human immunodeficiency virus type 1 (HIV-1)-mediated fusion events. One of them, T20 (aa 638-673), was found disordered and sparingly soluble in water, but became soluble upon mixing with selected, structured peptides from the amino terminal heptad repeat (HR1) region of gp41 using a simple and sensitive method of reduction in the scattering of T20 suspension. From the results on mapping the locus of interaction with T20 by employing partially overlapping peptides derived from HR1, it was concluded that the LLSGIV segment was a critical docking site for the C-terminal peptide of gp41 in its putative inhibitory action consistent with a previous fluorescence study. It was also found that peptides capable of solubilizing T20 dispersion have a high content of helix, as well as beta-strand, conformation in aqueous solution. Specificity of T20/HR1-derived peptide binding was ascertained by using a scrambled sequence of a T20-active peptide and a plateau in scattering reduction of T20 suspension with variation in the concentration of a T20-active HR1 peptide. Implications on the mechanism of T20 inhibition and the sequence of folding of the gp41 core structure are discussed.
Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Vishwa Deo
VD
Trivedi
Shu-Fang
SF
Cheng
Cheng-Wei
CW
Wu
Radhakrishnan
R
Karthikeyan
Chen-Jui
CJ
Chen
Ding-Kwo
DK
Chang
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D015195:Drug Design; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009391:Nephelometry and Turbidimetry; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012995:Solubility; D020079:Terminal Repeat Sequences
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide