The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-(N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with α_vβ₃, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce α_vβ₃ allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved α_vβ₃-binding properties and devoid of adverse integrin-activating effects.

中文翻译：

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丁二酰亚胺为基础的结合物提高IsoDGR环肽亲到α _v β ₃而不促进整合变构性活化

isoDGR序列是整联蛋白结合基序，已成功用作肿瘤血管结构归巢分子或用于将药物和诊断剂靶向递送至肿瘤。在这种情况下，我们以前证明了环肽2，即c（CGisoDGRG）（1）与4-（N-马来酰亚胺甲基）环己烷-1-羧酰胺缀合的产物，可以成功地用作纳米药物的肿瘤归巢配体。传递到肿瘤组织。这里，结合NMR，计算，和生物化学方法，我们表明，琥珀酰亚胺环中含有2有助于稳定的相互作用与α _v β ₃，在肿瘤血管中过度表达的整合素。此外，我们证明了包含嵌入在不同的分子骨架的isoDGR序列不同环肽不诱导α _v β ₃的变构激活和工作作为纯整联蛋白拮抗剂。这些结果可以被有益地开发用于新的基于isoDGR配体和肿瘤靶向分子的合理设计具有改进的α _v β ₃ -结合性质并且没有不利的整合素活化的效果。