title: Paradoxical downregulation of CXC chemokine receptor 4 induced by polyphemusin II-derived antagonists.
abstract: CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor implicated in cell entry of T-cell line-tropic HIV-1 strains. CXCR4 and its ligand stromal cell derived factor-1 (SDF-1)/CXCL12 play pivotal parts in many physiological processes and pathogenetic conditions (e.g., immune cell-homing and cancer metastasis). We previously developed the potent CXCR4 antagonist T140 from structure-activity relationship studies of the antimicrobial peptide polyphemusin II. T140 and its derivatives have been exploited in biological and biomedical studies for the SDF-1/CXCR4 axis. We investigated receptor localization upon ligand stimulation using fluorescent SDF-1 and T140 derivatives as well as a specific labeling technique for cellular-membrane CXCR4. Fluorescent T140 derivatives induced translocation of CXCR4 into the perinuclear region as observed by treatment with fluorescent SDF-1. T140 derivative-mediated internalization of CXCR4 was also monitored by the coiled-coil tag-probe system. These findings demonstrated that the CXCR4 antagonistic activity and anti-HIV activity of T140 derivatives were derived (at least in part) from antagonist-mediated receptor internalization.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Masuda
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanahara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yano
authors.forename: Katsumi
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Navenot
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D054377:Chemokine CXCL12 / Q000378:metabolism; D003412:Cricetulus; D015536:Down-Regulation / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C062386:polyphemusin II