title: Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity.
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 beta-sheet and a type II' beta-turn. A protuberance is formed on one side of the beta-sheet by the side-chain functional groups of the three amino acid residues (L-3-(2-naphthyl)alanine, 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. tamamura@pharm.kyoto-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Tamamura
authors.forename: M
authors.initials: M
authors.lastname: Sugioka
authors.forename: Y
authors.initials: Y
authors.lastname: Odagaki
authors.forename: A
authors.initials: A
authors.lastname: Omagari
authors.forename: Y
authors.initials: Y
authors.lastname: Kan
authors.forename: S
authors.initials: S
authors.lastname: Oishi
authors.forename: H
authors.initials: H
authors.lastname: Nakashima
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: S C
authors.initials: SC
authors.lastname: Peiper
authors.forename: N
authors.initials: N
authors.lastname: Hamanaka
authors.forename: A
authors.initials: A
authors.lastname: Otaka
authors.forename: N
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D019718:Receptors, CXCR4; C116977:T140 peptide