Title of article :
Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity
Author/Authors :
Hirokazu Tamamura، نويسنده , , Makiko Sugioka، نويسنده , , Yoshihiko Odagaki، نويسنده , , Akane Omagari، نويسنده , , Yukiko Kan، نويسنده , , Shinya Oishi، نويسنده , , Hideki Nakashima، نويسنده , , Naoki Yamamoto، نويسنده , , Stephen C. Peiper، نويسنده , , Nobuyuki Hamanaka، نويسنده , , Akira Otaka، نويسنده , , Nobutaka Fujii*، نويسنده ,
Abstract :
We report the solution structure of T140, a truncated polyphemusin peptide analogue that efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 through its specific binding to a chemokine receptor, CXCR4. Nuclear magnetic resonance analysis and molecular dynamic calculations revealed that T140 has a rigidly structured conformation constituted by an antiparallel β-sheet and a type II′ β-turn. A protuberance is formed on one side of the β-sheet by the side-chain functional groups of the three amino acid residues ( -3-(2-naphthyl)alanine3, Tyr5 and Arg14), each of which is indispensable for strong anti-HIV activity. These findings provide a rationale to dissect the structural basis for the ability of this compound to block the interaction between CXCR4 and envelope glycoproteins from T-tropic strains of HIV-1.
