A chemokine receptor CXCR4 belongs to the G-protein coupled receptor (GPCR) family. Interaction with its endogenous ligand, stromal-cell derived factor-la (SDF-1)/CXCL12, induces various physiological functions in an embryonic stage. Recent studies have indicated a pivotal role of homo-and hetero-oligomerization of CXCR4 in cancer metastasis. In the previous study, we have designed and synthesized novel CXCR4 bivalent ligands utilizing two FC131 analogues [cyc/o(-D-Tyr-Arg-Arg-Nal-D-Cys-)](Nal = L-3-(2-naphthyl)alanine) as ligand units [1]. The units are connected by a polyproline or a PEGylated polyproline linker. A ligand with an optimum linker-length showed the strongest binding affinity. Thus the dimer-state of CXCR4 on the cell surface was estimated by the linker length. FACS analyses showed that the bivalent ligand can distinguish the amount of CXCR4 expression. As the next challenge, migration of cells was targeted by the bivalent ligands because it was unclear whether the binding of CXCR4 bivalent ligands can promote or suppress the migration induced by the chemotaxis depending on the concentration of SDF-la.
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