Synthesis and characterization of a high-affinity {alpha}v{beta}6-specific ligand for in vitro and in vivo applications.
Synthesis and characterization of a high-affinity {alpha}v{beta}6-specific ligand for in vitro and in vivo applications.
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DOI：
10.1158/1535-7163.mct-08-1098
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
Brown KC
中科院分区：
文献类型：
--
作者：
Li S;McGuire MJ;Lin M;Liu YH;Oyama T;Sun X;Brown KC
α-v-β-6整合素因其在肿瘤转移中的作用和在正常组织中可忽略的表达而成为几种癌症的治疗靶点。我们先前从噬菌体展示的多肽文库中发现了一个与αvβ6特异结合的多肽。该多肽的四聚体版本与其细胞靶标的亲和力高于相应的单体。然而，低效率的合成限制了它的临床潜力。本文报道了一种高产率、高纯度的四聚体肽的聚合合成方法。合成的简便性使得多肽的快速优化成为可能。我们优化了αvβ6整合素结合肽，确定了最小结合结构域和价态。重要的是，最佳肽与其靶细胞的半最大结合亲和力在40至60pmol/L范围内，与常用的抗体靶向试剂的亲和力相当。这种多肽介导细胞特异性摄取，具有诊断功能，在血清中稳定，并可在动物体内形成肿瘤。我们预计，这种针对αvβ6的高亲和力配体将被用作临床诊断和治疗试剂。
The αvβ6 integrin is an attractive therapeutic target for several cancers due to its role in metastasis and its negligible expression in normal tissues. We previously identified a peptide from a phage-displayed peptide library that binds specifically to αvβ6. The tetrameric version of the peptide has higher affinity for its cellular targets than the corresponding monomers. However, the inefficient synthesis limits its clinical potential. We report here a convergent synthesis producing the tetrameric peptide in high yield and purity. The ease of the synthesis allows for rapid optimization of the peptide. We have optimized this αvβ6 integrin–binding peptide, determining the minimal binding domain and valency. Importantly, the half-maximal binding affinity of the optimal peptide for its target cell is in the 40 to 60 pmol/L range, rivaling the affinity of commonly used antibody-targeting reagents. This peptide mediates cell-specific uptake, is functional in diagnostic formats, is stable in sera, and can home to a tumor in an animal. We anticipate that this high-affinity ligand for αvβ6 will find clinical use as a diagnostic and therapeutic reagent.