| Research Abstract |
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.
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