Cell-Penetrating Peptides-Mechanisms of Cellular Uptake and Generation of Delivery Systems.
Cell-Penetrating Peptides-Mechanisms of Cellular Uptake and Generation of Delivery Systems.
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DOI：
10.3390/ph3040961
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发表时间：
2010-03-30
期刊：
影响因子：
--
通讯作者：
De Lima MC
中科院分区：
文献类型：
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作者：
Trabulo S;Cardoso AL;Mano M;De Lima MC
以核酸为基础的治疗策略的成功临床应用受到现有载体递送效率较低的限制。因此，为改善生物活性而开发替代输送系统是强制性的。自从二十年前TAT蛋白及其衍生的多肽可以跨生物膜转运的开创性观察以来，细胞穿透肽(CPPs)一直被认为是改善治疗分子非侵入性细胞递送的最有前途的工具之一。尽管对CPP用于这一目的进行了广泛的研究，但其细胞摄取和多肽结合物的确切机制仍然存在争议。在过去的几年里，我们的研究小组一直专注于S413-PV细胞穿透肽，这是这类多肽的原型，它是由Dermaseptin S4多肽衍生的13个氨基酸的细胞穿透序列与SV40大T抗原核定位信号结合而成的。通过对该多肽及其类似物进行广泛的生物物理和生化表征，我们对多肽与细胞的相互作用及其跨生物膜转运的机制有了重要的了解。最近，我们开始探索这种多肽用于细胞内核酸(质粒DNA、siRNA和寡核苷酸)的传递。在这篇综述中，我们讨论了目前对细胞摄取穿透性多肽的机制的了解，包括S413-PV多肽，以及基于多肽的制剂介导核酸递送的可能性。
The successful clinical application of nucleic acid-based therapeutic strategies has been limited by the poor delivery efficiency achieved by existing vectors. The development of alternative delivery systems for improved biological activity is, therefore, mandatory. Since the seminal observations two decades ago that the Tat protein, and derived peptides, can translocate across biological membranes, cell-penetrating peptides (CPPs) have been considered one of the most promising tools to improve non-invasive cellular delivery of therapeutic molecules. Despite extensive research on the use of CPPs for this purpose, the exact mechanisms underlying their cellular uptake and that of peptide conjugates remain controversial. Over the last years, our research group has been focused on the S413-PV cell-penetrating peptide, a prototype of this class of peptides that results from the combination of 13-amino-acid cell penetrating sequence derived from the Dermaseptin S4 peptide with the SV40 large T antigen nuclear localization signal. By performing an extensive biophysical and biochemical characterization of this peptide and its analogs, we have gained important insights into the mechanisms governing the interaction of CPPs with cells and their translocation across biological membranes. More recently, we have started to explore this peptide for the intracellular delivery of nucleic acids (plasmid DNA, siRNA and oligonucleotides). In this review we discuss the current knowledge of the mechanisms responsible for the cellular uptake of cell-penetrating peptides, including the S413-PV peptide, and the potential of peptide-based formulations to mediate nucleic acid delivery.