Tamamura Hirokazu, Tsutsumi Hiroshi, Nomura Wataru, Fujii Nobutaka
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
Perspect Medicin Chem. 2008 Feb 10;2:1-9. doi: 10.4137/pmc.s422.
Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor-1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing.
七跨膜（7TM）G蛋白偶联受体（GPCR）家族是药物研发的重要靶点，GPCR的特异性拮抗剂可加速药物化学领域的研究。趋化因子受体CXCR4是一种GPCR，其具有独特的配体CXCL12/基质细胞衍生因子-1（SDF-1）。CXCL12与CXCR4之间的相互作用对于心血管、造血和中枢神经系统胚胎发育过程中祖细胞的迁移至关重要，并且还参与了多种难治性疾病过程，包括HIV感染、癌细胞转移、急慢性白血病进展、类风湿性关节炎和肺纤维化。因此，CXCR4可能是所有这些疾病中的一个重要治疗靶点，并且已经提出了各种CXCR4拮抗剂作为潜在药物。我们已经开发出十四肽、T140及其类似物以及小型化环五肽作为有效的CXCR4拮抗剂。本文描述了我们实验室中多种特异性CXCR4拮抗剂的研发情况，包括小型化。
