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.
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.
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
Omagari
Akane
A
Hiramatsu
Kenichi
K
Oishi
Shinya
S
Habashita
Hiromu
H
Kanamoto
Taisei
T
Gotoh
Kazuyo
K
Yamamoto
Naoki
N
Nakashima
Hideki
H
Otaka
Akira
A
Fujii
Nobutaka
N
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
C473369:3-(2-naphthyl)alanine; D019380:Anti-HIV Agents; D009281:Naphthalenes; D009842:Oligopeptides; D019718:Receptors, CXCR4; C059031:1-naphthylalanine; C116977:T140 peptide; D000409:Alanine