Hirokazu Tamamura¹, Yuko Yamada¹, Tomohiro Tanaka¹, Hiroshi Tsutsumi¹, Shinya Oishi² and Nobutaka Fujii²

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Tokyo¹, and Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan²

As the clinical treatment of AIDS or HIV-1-infected patients, HAART, which uses a combination of reverse transcriptase inhibitors and protease inhibitors, has brought us a significant success. A fusion inhibitor, enfuvirtide (DP-178, T-20, Fuzeon, Trimers & Roche), has also been clinically used. However, there still remain several serious problems, which involve the emergence of viral strains with multi-drug resistance (MDR). Thus, development of novel drugs possessing action mechanisms different from the above inhibitors would be currently desirable. We have previously developed selective antagonists against the chemokine receptor CXCR4, which is identified as a co-receptor of a T cell line-tropic (X4-) HIV-1 entry. CXCR4, which is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1), has multiple important functions in normal and pathological physiology. The CXCL12-CXCR4 axis has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA) and pulmonary fibrosis. Thus, CXCR4 is a great drug target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were identified as HIV-1 inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. T140 analogs have been proven to strongly block an X4-HIV-1 entry through their specific binding to CXCR4. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were previously found as CXCR4 antagonists based on pharmacophores of T140. T140-related compounds have several great advantages such as the difficulty of the generation of drug-resistant strains in vitro. In this seminar, we would like to report the development of new classes of low molecular weight CXCR4 antagonists.