title: Certification of the critical importance of L-3-(2-naphthyl)alanine at position 3 of a specific CXCR4 inhibitor, T140, leads to an exploratory performance of its downsizing study.
abstract: We have previously found that a 14-amino acid residue-peptide, T140, inhibits infection of target cells by T cell line-tropic HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. Here, the importance of an L-3-(2-naphthyl)alanine (Nal) residue at position 3 in T140 for high anti-HIV activity and inhibitory activity against Ca(2+) mobilization induced by stromal cell-derived factor (SDF)-1alpha-stimulation through CXCR4 has initially been shown by the synthesis and biological evaluation of several analogues, where Nal(3) is substituted by diverse aromatic amino acids. Next, the order of the N-terminal 3 residues (Arg(1)-Arg(2)-Nal(3)) has been proved to be important from the structure--activity relationship (SAR) study shuffling these residues. Based on these results, we have found 10-residue peptides possessing modest anti-HIV activity by systematic antiviral evaluation of a series of synthetic, shortened analogues of T140.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Akane
authors.initials: A
authors.lastname: Omagari
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Taisei
authors.initials: T
authors.lastname: Kanamoto
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Gotoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000821:virology
chemical_list: C473369:3-(2-naphthyl)alanine; D019380:Anti-HIV Agents; D009281:Naphthalenes; D009842:Oligopeptides; D019718:Receptors, CXCR4; C059031:1-naphthylalanine; C116977:T140 peptide; D000409:Alanine