title: Biophysical evidence of two docking sites of the carboxyl heptad repeat region within the amino heptad repeat region of gp41 of human immunodeficiency virus type 1.
abstract: Two HIV-1 gp41-derived peptide fusion inhibitors, T-20 and T-649, were synthesized and their binding profiles of the N-heptad repeat region (HR1) were compared to examine the molecular basis of the differential antiviral potency and viral resistance. Turbidity clearance experiments based on the overlapping 15-mer peptides derived from HR1 revealed a major binding site at the LLSGIV segment for both T-20 and T-649. Additionally, another docking site was found at the sequence encompassing the hydrophobic pocket of HR1 for T-649. Concordant results were observed from the surface plasmon resonance measurements. The binding affinity profile exhibited a major maximum around the LLSGIV motif for the two peptide fusion inhibitors while a less prominent docking region was located near the hydrophobic pocket for T-649. This bi-modal model deduced from T-20 and T-649 interaction with HR1 peptides could rationalize the failure of emergence of the fusion inhibitor-resistant virus with simultaneous mutations in each of the two binding regions, as well as the generally higher potency of T-649 against most viral strains.
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan, Republic of China. dkc@chem.sinica.edu.tw
authors.forename: Ding-Kwo
authors.initials: DK
authors.lastname: Chang
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Hsu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000032:analysis* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D009391:Nephelometry and Turbidimetry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C435505:T-649 peptide; D000077560:Enfuvirtide