title: Interactions between different generation HIV-1 fusion inhibitors and the putative mechanism underlying the synergistic anti-HIV-1 effect resulting from their combination.
abstract: We previously reported that the combinatorial use of T20 and T1144, the first and next generations of HIV fusion inhibitors, containing different functional domains resulted in synergistic anti-HIV-1 effect, but this effect diminished when T20 and T1144 were covalently linked together. To elucidate the mechanism underlying this synergistic anti-HIV-1 effect, we studied the interactions between T20 and T1144 either in a mixture state or in a covalently linked state. T20 alone in solution was largely featureless, while T1144 alone was in α-helical trimeric conformation. When mixed in solution, T20 and T1144 showed a loose and transient interaction, with a moderate 10% α-helical content increase, but this interaction was greatly enhanced in the linked state, and T20 and T1144 showed ∼100% α-helical content. These results suggested that the loose and transient interaction between T20 and T1144 may destabilize the T1144 trimer, which makes its otherwise shielded binding sites more accessible to N-terminal heptad repeat (NHR) and increases its associating rate, thus increasing its anti-HIV-1 potency against the temporarily exposed target in NHR and causing the synergistic anti-HIV-1 effect. However, the strong interaction between T20 and T1144 in the covalently linked state may shield their NHR-binding sites, resulting in reduction of the synergistic effect.
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Cai
authors.forename: Chungen
authors.initials: C
authors.lastname: Pan
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shui
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010455:Peptides; C572250:T1144 peptide; D000077560:Enfuvirtide
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