Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
Department of Chemistry, Texas A&M University, College Station, TX 77845, USA.
Biomolecules. 2018 Jul 11;8(3):50. doi: 10.3390/biom8030050.
Cell-penetrating peptides (CPPs) are typically prone to endocytic uptake into human cells. However, they are often inefficient at escaping from endosomes, which limits their ability to deliver cargos into cells. This review highlights the efforts that our laboratory has devoted toward developing CPPs that can mediate the leakage of endosomal membranes, and consequently gain better access to the intracellular milieu. In particular, we have identified a CPP named dimeric fluorescent TAT (dfTAT) with high endosomolytic activity. We describe how we have used this reagent and its analogs to develop efficient cytosolic delivery protocols and learn about molecular and cellular parameters that control the cell permeation process. Specifically, we discuss how late endosomes represent exploitable gateways for intracellular entry. We also describe how certain features in CPPs, including guanidinium content, charge density, multimerization, chirality, and susceptibility to degradation modulate the activity that these peptidic agents take toward endosomal membranes and cytosolic egress.
细胞穿透肽（CPPs）通常容易被内吞作用进入人体细胞。然而，它们通常从内涵体中逃逸的效率较低，这限制了它们将货物递送到细胞内的能力。这篇综述强调了我们实验室在开发能够介导内涵体膜渗漏的 CPP 方面所做的努力，从而更好地进入细胞内环境。特别是，我们已经确定了一种名为二聚体荧光 TAT（dfTAT）的 CPP，具有很高的内涵体溶解活性。我们描述了如何使用这种试剂及其类似物来开发有效的细胞质递送方案，并了解控制细胞渗透过程的分子和细胞参数。具体来说，我们讨论了晚期内涵体如何代表细胞内进入的可利用的门户。我们还描述了 CPP 中的某些特征，包括胍基含量、电荷密度、多聚化、手性和对降解的敏感性，如何调节这些肽类试剂对内涵体膜和细胞质流出的活性。
