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Biomolecules 2018, 8(3), 50; https://doi.org/10.3390/biom8030050

Efficient Delivery of Macromolecules into Human Cells by Improving the Endosomal Escape Activity of Cell-Penetrating Peptides: Lessons Learned from dfTAT and its Analogs

1
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
2
Department of Chemistry, Texas A&M University, College Station, TX 77845, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 23 June 2018 / Revised: 5 July 2018 / Accepted: 6 July 2018 / Published: 11 July 2018
(This article belongs to the Special Issue Cell Penetrating Peptides)
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Abstract

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. View Full-Text
Keywords: peptide; cell-penetrating peptide; cellular delivery; endosomal escape; membrane leakage; TAT peptide; multimerization; chirality; charge density peptide; cell-penetrating peptide; cellular delivery; endosomal escape; membrane leakage; TAT peptide; multimerization; chirality; charge density
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Allen, J.K.; Brock, D.J.; Kondow-McConaghy, H.M.; Pellois, J.-P. Efficient Delivery of Macromolecules into Human Cells by Improving the Endosomal Escape Activity of Cell-Penetrating Peptides: Lessons Learned from dfTAT and its Analogs. Biomolecules 2018, 8, 50.

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