Paradoxical Downregulation of CXC Chemokine Receptor 4 Induced by Polyphemusin II-Derived Antagonists

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• 作者：Ryo Masuda ; Shinya Oishi ; Noriko Tanahara ; Hiroaki Ohno ; Akira Hirasawa ; Gozoh Tsujimoto ; Yoshiaki Yano ; Katsumi Matsuzaki ; Jean-Marc Navenot ; Stephen C. Peiper ; Nobutaka Fujii
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：June 20, 2012
• 年：2012
• 卷：23
• 期：6
• 页码：1259-1265
• 全文大小：383K
• 年卷期：v.23,no.6(June 20, 2012)
• ISSN：1520-4812

文摘

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鈥揳ctivity 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.