Cyclic RGD-Containing Functionalized Azabicycloalkane Peptides as Potent Integrin Antagonists for Tumor Targeting
Cyclic RGD-Containing Functionalized Azabicycloalkane Peptides as Potent Integrin Antagonists for Tumor Targeting
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DOI：
10.1002/cmdc.200800422
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发表时间：
2009-04-01
期刊：
影响因子：
3.4
通讯作者：
Scolastico, Carlo
中科院分区：
文献类型：
--
作者：
Manzoni, Leonardo;Belvisi, Laura;Scolastico, Carlo
为了开发高亲和力的选择性整合素配体作为治疗和诊断的载体，合成了含有RGD功能的环二氮杂环烷基多肽。在这里，我们描述了这些RGD衍生物的合成和体外筛选，以及用光谱和计算方法测定它们在溶液中的构象性质。还进行了与整合素胞外域α(V)β(3)的X射线晶体结构的对接研究，以阐明结构结合要求并使生物学结果合理化。在新的功能化RGD环肽中，有一种化合物被发现是最好的α(V)β(3)整合素结合剂(IC50=53.7 nM)，因此有望成为共价键和有用功能单元的选择性归位的候选化合物。
Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC50=53.7nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.