Organelle-targeted delivery of biological macromolecules using the protein transduction domain: Potential applications for peptide aptamer delivery into the nucleus
Organelle-targeted delivery of biological macromolecules using the protein transduction domain: Potential applications for peptide aptamer delivery into the nucleus
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DOI：
10.1016/j.jmb.2008.05.047
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发表时间：
2008-07-25
影响因子：
5.6
通讯作者：
Tsutsumi, Yasuo
中科院分区：
文献类型：
--
作者：
Yoshikawa, Tomoaki;Sugita, Toshiki;Tsutsumi, Yasuo
目前正在花费大量的努力来创新设计和工程化新的分子载体系统，用于生物货物（例如，肽适体或生物蛋白质）作为细胞生物学中的工具和用于开发新的治疗方法。尽管细胞可渗透的达特肽是用于将生物分子递送到细胞中的有用载体，但许多内化的塔特融合货物被捕获在大胞饮体内，因此不能递送到细胞器中。在这里，我们设计了一种新的细胞内靶向技术，使用内体破坏性肽（血凝素-2亚基）和核定位信号肽将Tat融合的货物递送到细胞核中。我们首次表明，Tat缀合的肽适体可以通过使用组合的血凝素-2亚基和核定位信号肽选择性地递送到细胞核。这种核靶向技术导致Tat融合的p53衍生肽适体针对人MDM 2（小鼠双微体2）的抑制p53-MDM 2结合的细胞抑制活性显著增强。因此，我们的技术为开发基于细胞内靶向的新型治疗方法提供了独特的方法。(C)2008爱思唯尔有限公司保留所有权利。
Extensive effort is currently being expended on the innovative design and engineering of new molecular carrier systems for the organelle-targeted delivery of biological cargoes (e.g., peptide aptamers or biological proteins) as tools in cell biology and for developing novel therapeutic approaches. Although cell-permeable Tat peptides are useful carriers for delivering biological molecules into the cell, much internalized Tat-fused cargo is trapped within macropinosomes and thus not delivered into organelles. Here, we devised a novel intracellular targeting technique to deliver Tat-fused cargo into the nucleus using an endosome-disruptive peptide (hemagglutinin-2 subunit) and a nuclear localization signal peptide. We show for the first time that Tat-conjugated peptide aptamers can be selectively delivered to the nucleus by using combined hemagglutinin-2 subunit and nuclear localization signal peptides. This nuclear targeting technique resulted in marked enhancement of the cytostatic activity of a Tat-fused p53-derived peptide aptamer against human MDM2 (mouse double minute 2) that inhibits p53-MDM2 binding. Thus, our technique provides a unique methodology for the development of novel therapeutic approaches based on intracellular targeting. (C) 2008 Elsevier Ltd. All rights reserved.