Histidine-Iridium(III) Coordination-Based Peptide Luminogenic Cyclization and Cyclo-RGD Peptides for Cancer-Cell Targeting
Histidine-Iridium(III) Coordination-Based Peptide Luminogenic Cyclization and Cyclo-RGD Peptides for Cancer-Cell Targeting
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用于癌细胞靶向的基于组氨酸-铱 (III) 配位的肽发光环化和环-RGD 肽
DOI：
10.1021/ja511656q
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发表时间：
2014-12-24
影响因子：
15
通讯作者：
Fei, Hao
中科院分区：
文献类型：
--
作者：
Ma, Xiaochuan;Jia, Junli;Fei, Hao
在多肽药物发现领域，结构约束和荧光标记是两种备受追捧的技术，对于基础研究和药物开发都很重要。在这项工作中，我们描述了一种易于使用的方法，同时肽环化和发光标记的基础上铱（III）-组氨酸配位（Ir-HH环化）。使用一系列的模型肽与组氨酸侧翼的每个末端，结合活性和反应动力学的Ir-HH环化的不同环大小的特点。在该系列中，具有中等环尺寸的Ir-HAnH（n = 2，3）提供了用于环状形成的组氨酸之间的适当的柔性和适当的距离，这导致在生理条件下的最佳结合亲和力和结构稳定性，与具有较小（n = 0，1）或较大（n = 4，5）环尺寸的其他Ir-HH-环化肽相比。Ir-HRGDH是一种含有整合素靶向基序Arg-Gly-Asp（RGD）的Ir-HH环化肽，与荧光素标记的环状RGDyK肽相比，其表现出比其线性形式更好的靶向亲和力和增强的膜通透性。细胞死亡诱导肽KLA-连接的Ir-HRGDH（Ir-HRGDH-KLA）显示出显著增强的细胞毒性和对癌细胞相对于非癌细胞的高选择性。这些数据表明，该方法方便地将肽的结构约束与发光成像能力相结合，这有利于潜在的基于肽的药物先导物的功能和细胞内表征，从而引入了一种新的工具来满足医学研究中的新兴需求。
In the field of peptide drug discovery, structural constraining and fluorescent labeling are two sought-after techniques important for both basic research and pharmaceutical development. In this work, we describe an easy-to-use approach for simultaneous peptide cyclization and luminescent labeling based on iridium(III)-histidine coordination (Ir-HH cyclization). Using a series of model peptides with histidine flanking each terminus, the binding activity and reaction kinetics of Ir-HH cyclization of different ring sizes were characterized. In the series, Ir-HAnH (n = 2, 3) with moderate ring sizes provides appropriate flexibility and proper distance between histidines for cyclic formation, which leads to the best binding affinity and structural stability in physiological conditions, as compared to other Ir-HH-cyclized peptides with smaller (n = 0, 1) or larger (n = 4, 5) ring sizes. Ir-HRGDH, an Ir-HH-cyclized peptide containing integrin targeting motif Arg-Gly-Asp (RGD), showed better targeting affinity than its linear form and enhanced membrane permeability in comparison with fluorescein-labeled cyclic RGDyK peptide. Cell death inducing peptide KLA-linked Ir-HRGDH (Ir-HRGDH-KLA) showed dramatically enhanced cytotoxicity and high selectivity for cancer cells versus noncancer cells. These data demonstrate that the method conveniently combines structural constraining of peptides with luminescent imaging capabilities, which facilitates functional and intracellular characterization of potential peptide-based drug leads, thus introducing a new tool to meet emerging needs in medicinal research.