Identification of a CXCR4 antagonist, a T140 analog, as an anti‐rheumatoid arthritis agent
Identification of a CXCR4 antagonist, a T140 analog, as an anti‐rheumatoid arthritis agent
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DOI：
10.1016/j.febslet.2004.05.056
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发表时间：
2004-07
期刊：
影响因子：
3.5
通讯作者：
H. Tamamura;Miho Fujisawa;K. Hiramatsu;Makiko Mizumoto;H. Nakashima;N. Yamamoto;A. Otaka;N. Fujii
中科院分区：
文献类型：
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作者：
H. Tamamura;Miho Fujisawa;K. Hiramatsu;Makiko Mizumoto;H. Nakashima;N. Yamamoto;A. Otaka;N. Fujii
最近的几篇论文支持基质细胞衍生因子 1 (SDF-1/CXCL12) 与其受体趋化因子受体 CXCR4 之间的相互作用参与炎症类风湿性关节炎 (RA) 滑膜中记忆 T 细胞的迁移。之前发现 14 聚体肽 T140 的类似物是特异性 CXCR4 拮抗剂，其特征不仅是 HIV 进入抑制剂，而且是抗癌转移剂。在这项研究中，T140类似物4F-苯甲酰-TN14003被证明能够在体外以剂量依赖性方式抑制CXCL12介导的人类Jurkat细胞和小鼠脾细胞的迁移（IC50分别为0.65和0.54 nM）。此外，使用Alzet渗透泵皮下注射（s.c.）缓释4F-苯甲酰-TN14003可显着抑制小鼠中绵羊红细胞诱导的迟发型超敏反应，并显着改善小鼠胶原诱导性关节炎的临床严重程度。因此，T140 类似物可能是 RA 化疗中有吸引力的先导化合物。
Several recent papers support the involvement of an interaction between stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, chemokine receptor CXCR4, in memory T cell migration in the inflamed rheumatoid arthritis (RA) synovium. Analogs of the 14-mer peptide T140 were previously found to be specific CXCR4 antagonists that were characterized as not only HIV-entry inhibitors but also anti-cancer-metastatic agents. In this study, a T140 analog, 4F-benzoyl-TN14003, was proven to inhibit CXCL12-mediated migration of human Jurkat cells and mouse splenocyte in a dose-dependent manner in vitro (IC50=0.65 and 0.54 nM, respectively). Furthermore, slow release administration by subcutaneous injection (s.c.) of 4F-benzoyl-TN14003 using an Alzet osmotic pump significantly suppressed the delayed-type hypersensitivity response induced by sheep red blood cells in mice, and significantly ameliorated clinical severity in collagen-induced arthritis in mice. As such, T140 analogs might be attractive lead compounds for chemotherapy of RA.