Development of Chemokine Receptor CXCR4 Antagonists Using Bio-mimetic Strategy

摘要

G-protein-coupled receptor (GPCR) families form great drug targets in medicinal chemistry in the post-genome era. Chemokine receptors are classified into GPCR families. A chemokine receptor CXCR4 has multiple critical functions in normal and pathologic physiology. CXCR4 transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 axis plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems and so on. This 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 [1]. Thus, CXCR4 is a great therapeutic 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-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents [2]. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were previously found as CXCR4 antagonist leads based on pharmacophores of T140 [3]. Here is described the development of low molecular weight CXCR4 antagonists based on FC131 [4].