Membrane Crossing and Membranotropic Activity of Cell- Penetrating Peptides: Dangerous Liaisons?

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Membrane Crossing and Membranotropic Activity of Cell-Penetrating Peptides: Dangerous Liaisons?, Acc. Chem. Research2017


Living organisms have to maintain a stable balance in molecules and ions in the changing environment in which they are living, a process known as homeostasis. At the level of cells, the plasma membrane has a major role in homeostasis, since this hydrophobic film prevents passive diffusion of large and hydrophilic molecules between the extracellular and intracellular milieu. Living organisms have evolved with highly sophisticated transport systems to control exchanges across this barrier: import of nutrients and fuel essential for their survival; recognition of chemical or physical messengers allowing information interchanges with surrounding cells. Besides specialized proteins, endocytosis mechanisms at the level of the lipid bilayer can transport molecules from the outside across the cell membrane, in an energy-dependent manner.



We described methods and the complex study of membrane crossing of cell-penetrating peptides, a question that remains open in the fi eld. One particular point we have not discussed in this Account relates to the lack of selective entry of CPPs in cells. This is obviously not the case, for example, for homeoproteins, highly specialized transcription factors that transfer from cell to cell. Some homeoproteins show, for instance, selective entry into specific neuronal cells in the central nervous system of animals. Since these proteins include very specialized and independent peptide domains with defined functions, we should take advantage of those to identify protein domains that would help CPPs to target specifi cally cell surface molecules and enhance their selectivity.





Acc. Chem. Research2017


In this Account, we focus on cationic cell-penetrating peptides (CPPs) and the way they cross cell membranes. We summarize the history of this fi eld that emerged around 20 years ago. CPPs were indeed fi rst identifi ed as protein-transduction domains from the human immunodefi ciency virus (HIV) TAT protein and the Antennapedia homeoprotein, a transcription factor from Drosophila. We highlight our contribution to the elucidation of CPP internalization pathways, in particular translocation, which implies perturbation and reorganization of the lipid bilayer, and endocytosis depending on sulfated glycosaminoglycans. We show a particular role of Trp (indole side chain) and Arg (guanidinium side chain), which are essential amino acids for CPP internalization. Interactions with the cell-surface are not only Coulombic; H-bonds and hydrophobic interactions contribute also significantly to CPP entry. The capacity of CPPs to cross cell membrane is not related to their strength of membrane binding. Finally, we present optimized methods based on mass spectrometry and fluorescence spectroscopy that allow unequivocal quantification of CPPs inside cells or bound to the outer leafl et of the membrane, and discuss some limitations of the technique of flow cytometry that we have recently highlighted.

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Membrane Crossing and Membranotropic Activity of Cell-Penetrating Peptides: Dangerous Liaisons?


Astrid Walrant, Sébastien Cardon, Fabienne Burlina, and Sandrine Sagan


Acc. Chem. Research, 2017


DOI: 10.1021/acs.accounts.7b00455