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. © 2007 Elsevier B.V. All rights reserved.
Chang, D. K., & Hsu, C. S. (2007). 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. Antiviral Research, 74(1), 51–58. https://doi.org/10.1016/j.antiviral.2006.12.006