Activation of Cell-Penetrating Peptides with Ionpair−π Interactions and Fluorophiles
| Autor: | Nicolas Winssinger, Stefan Matile, Giuseppe Resnati, Naomi Sakai, Pierangelo Metrangolo, Kaori Fujisawa, Jacques Saarbach, Paola Morelli, Nicolas Chuard |
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| Rok vydání: | 2016 |
| Předmět: |
Endosome
Cell Nanotechnology Cell-Penetrating Peptides 010402 general chemistry Antiparallel (biochemistry) 01 natural sciences Biochemistry Catalysis chemistry.chemical_compound Colloid and Surface Chemistry Amphiphile medicine Humans High activity Fluorocarbons Pyrenes 010405 organic chemistry General Chemistry 0104 chemical sciences medicine.anatomical_structure Membrane chemistry Drug Design ddc:540 Biophysics Pyrene Hydrophobic and Hydrophilic Interactions HeLa Cells |
| Zdroj: | Journal of the American Chemical Society, Vol. 138, No 35 (2016) pp. 11264-11271 Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | In this report, we elaborate on two new concepts to activate arginine-rich cell-penetrating peptides (CPPs). Early on, we have argued that repulsion-driven ion-pairing interactions with anionic lipids account for their ability to move across hydrophobic cell membranes and that hydrophobic anions such as pyrenebutyrate can accelerate this process to kinetically outcompete endosomal capture. The original explanation that the high activity of pyrenebutyrate might originate from ionpair-π interactions between CPP and activator implied that replacement of the π-basic pyrene with polarized push-pull aromatics should afford more powerful CPP activators. To elaborate on this hypothesis, we prepared a small collection of anionic amphiphiles that could recognize cations by ionpair-π interactions. Consistent with theoretical predictions, we find that parallel but not antiparallel ionpair-π interactions afford operational CPP activators in model membranes and cells. The alternative suggestion that the high activity of pyrenebutyrate might originate from self-assembly in membranes was explored with perfluorinated fatty acids. Their fluorophilicity was expected to promote self-assembly in membranes, while their high acidity should prevent charge neutralization in response to self-assembly, i.e., generate repulsion-driven ion-pairing interactions. Consistent with these expectations, we find that perfluorinated fatty acids are powerful CPP activators in HeLa cells but not in model membranes. These findings support parallel ionpair-π interactions and repulsion-driven ion pairing with self-assembled fluorophiles as innovative concepts to activate CPPs. These results also add much corroborative support for counterion-mediated uptake as the productive mode of action of arginine-rich CPPs. |
| Databáze: | OpenAIRE |
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