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
Jason K AllenJean-Philippe Pellois

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.

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Citations

Apr 23, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Friederike RichterAnja Traeger
Jul 21, 2020·Journal of Cellular Physiology·Mohsen MohammadiKhashayar Hesamizadeh
Apr 20, 2020·Journal of Biophotonics·Cuiping YaoRamtin Rahmanzadeh
Jun 17, 2020·Frontiers in Pharmacology·Ajay KumarRehan Khan
Jun 9, 2021·Journal of Peptide Science : an Official Publication of the European Peptide Society·Sujie HuangJingjing Song
Jul 21, 2021·ACS Applied Materials & Interfaces·Franziska HausigJohannes C Brendel
Nov 6, 2018·Langmuir : the ACS Journal of Surfaces and Colloids·Norihisa NakayamaKen-Ichi Sano
Mar 5, 2019·Bioconjugate Chemistry·Khushboo SinghS Thayumanavan
May 3, 2019·The Journal of Physical Chemistry. B·Yansheng YeConggang Li
Oct 2, 2020·ACS Central Science·Marco J LobbaMatthew B Francis
May 16, 2019·Chemical Reviews·Patrick G DoughertyDehua Pei
Dec 16, 2021·ELife·Wucheng TaoRoger A Nicoll

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Methods Mentioned

BETA
transfection

Software Mentioned

dfTAT

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