DEVELOPMENT OF CXCR4 ANTAGONISTS TARGETED TO ANTI-CANCER-METASTATIC AGENTS AND ANTI-HIV AGENTS

趋化因子受体CXCR 4是一种GPCR，可转导其内源性配体CXCL 12（基质细胞衍生因子-1，SDF-1）的信号。CXCL 12-CXCR 4系统最近已被证明参与几种有问题的疾病，包括HIV感染、癌细胞转移、白血病细胞进展和类风湿性关节炎（RA）：首先，CXCR 4被鉴定为用于T细胞嗜性（X4-）HIV-1进入的第二受体。第二，Muller等报道了CXCL 12-CXCR 4系统可能决定乳腺癌细胞的转移目的地。最近，已经认识到该系统涉及几种类型的癌症的转移，例如胰腺癌、黑色素瘤、前列腺癌、肾癌、神经母细胞瘤、非霍奇金淋巴瘤、肺癌、卵巢癌、多发性骨髓瘤和恶性脑肿瘤，以及慢性淋巴细胞白血病B细胞和前B急性淋巴细胞白血病细胞的进展。第三，Nanki等人指出，CXCL 12和CXCR 4之间的相互作用在RA滑膜中的T细胞积累中起关键作用。因此，CXCR 4被认为是克服上述疾病的重要治疗靶点。十四肽T140及其类似物是一种特异性CXCR 4拮抗剂，可作为HIV进入抑制剂、抗肿瘤转移剂、抗慢性淋巴细胞/急性淋巴细胞白血病剂和抗类风湿性关节炎剂。基于我们对T140药效团的了解，通过有效利用由基于构象和基于序列的文库组成的两个正交环状五肽文库，发现了CXCR 4拮抗剂，如FC 131。我们已经开发了包括FC 131类似物在内的低分子量CXCR 4拮抗剂，其中进行了环肽环的结构调整和化学修饰，以增加效力并降低肽特性。

The chemokine receptor, CXCR4, is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 system has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression and rheumatoid arthritis (RA) : First, CXCR4 was identified as a second receptor that is utilized in T cell line-tropic (X4-) HIV-1 entry. Second, Muller et al. reported that the CXCL12-CXCR4 system might determine the metastatic destination of breast cancer cells. Recently, this system has been recognized to be involved in the metastasis of several types of cancers, such as pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, multiple myeloma and malignant brain tumor, as well as in the progression of chronic lymphocytic leukemia B-cells and pre-B acute lymphoblastic leukemia cells. Third, Nanki et al. indicated that the interaction between CXCL12 and CXCR4 plays a critical role in T cell accumulation in the RA synovium. Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were characterized as HIV entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. Based on our knowledge of pharmacophores of T140, CXCR4 antagonists, such as FC131, were found by the efficient utilization of two orthogonal cyclic pentapeptide libraries consisting of conformation-based and sequence-based libraries. We have developed low molecular weight CXCR4 antagonists including FC131 analogs, in which structural tuning of the cyclic peptide ring and chemical modifications were performed for an increase in potency and a reduction of the peptide charcter.