Tanaka Tomohiro, Aoki Toru, Nomura Wataru, Tamamura Hirokazu
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
J Pept Sci. 2017 Jul;23(7-8):574-580. doi: 10.1002/psc.2946. Epub 2017 Jan 12.
Interaction of CXCR4 with its endogenous ligand, stromal-cell derived factor-1 (SDF-1)/CXCL12, induces various physiological functions involving chemotaxis. Bivalent ligands with a polyproline helix bearing a cyclic pentapeptide, FC131, were previously shown to have higher binding affinities for CXCR4 than the corresponding monovalent ligands. Bivalent ligands based on a 14-mer peptide T140 derivative with polyproline linkers have been designed and synthesized. The activity of these peptides as well as the effect of bivalency of the ligand on CXCR4 binding has been assessed. The binding affinity of these series of bivalent ligands is increased as the linker length increases up to the 12-/15-mer proline linker. The inhibitory activity against chemotaxis on Jurkat cells also depends on the linker length. The T140-derived bivalent ligands with the 9- and 12-mer proline linkers showed the most effective inhibition against chemotaxis at 1000 nM, which is even higher than that of known CXCR4 antagonists in the monomer structure. The effective metastatic inhibition by bivalent T140 derivatives indicates the therapeutic potential. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
CXCR4与其内源性配体基质细胞衍生因子-1（SDF-1）/CXCL12的相互作用可诱导包括趋化作用在内的多种生理功能。先前已证明，带有环五肽的聚脯氨酸螺旋二价配体FC131对CXCR4的结合亲和力高于相应的单价配体。基于带有聚脯氨酸接头的14肽T140衍生物设计并合成了二价配体。评估了这些肽的活性以及配体二价性对CXCR4结合的影响。随着接头长度增加至12/15聚脯氨酸接头，这一系列二价配体的结合亲和力增加。对Jurkat细胞趋化作用的抑制活性也取决于接头长度。带有9聚脯氨酸接头和12聚脯氨酸接头的T140衍生二价配体在1000 nM时对趋化作用表现出最有效的抑制，甚至高于单体结构中已知的CXCR4拮抗剂。二价T140衍生物有效的转移抑制作用表明了其治疗潜力。版权所有©2017欧洲肽学会和约翰·威利父子有限公司。
