Bivalent 14-mer Peptide Ligands of CXCR4 with Polyproline Linkers with Anti-Chemotactic Activity against Jurkat Cells
Bivalent 14-mer Peptide Ligands of CXCR4 with Polyproline Linkers with Anti-Chemotactic Activity against Jurkat Cells
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CXCR4 的二价 14 聚体肽配体与聚脯氨酸接头，具有针对 Jurkat 细胞的抗趋化活性
DOI：
10.1002/psc.2946
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hirokazu Tamamura
中科院分区：
文献类型：
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作者：
Tomohiro Tanaka;Toru Aoki;Wataru Nomura;Hirokazu Tamamura
CXCR 4与其内源性配体基质细胞衍生因子-1（SDF-1）/CXCL 12的相互作用诱导涉及趋化性的各种生理功能。具有带有环状五肽FC 131的聚脯氨酸螺旋的二价配体先前显示出比相应的单价配体对CXCR 4具有更高的结合亲和力。基于具有聚脯氨酸接头的14-mer肽T140衍生物的二价配体已经被设计和合成。已经评估了这些肽的活性以及配体的二价对CXCR 4结合的影响。随着接头长度增加至12-/15-mer脯氨酸接头，这些系列二价配体的结合亲和力增加。对Jurkat细胞上的趋化性的抑制活性也取决于接头长度。具有9-和12-mer脯氨酸接头的T140衍生的二价配体在1000 nM下显示出对趋化性的最有效抑制，其甚至高于单体结构中已知的CXCR 4拮抗剂。二价T140衍生物的有效转移抑制表明了治疗潜力。Copyright © 2017 European Peptide Society and John Wiley & Sons，Ltd.
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.