title: Activation of Cell-Penetrating Peptides with Ionpair-π Interactions and Fluorophiles.
abstract: 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.
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Nicolas
authors: N
authors: Chuard
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Kaori
authors: K
authors: Fujisawa
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Paola
authors: P
authors: Morelli
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Jacques
authors: J
authors: Saarbach
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Nicolas
authors: N
authors: Winssinger
authors: NFMLab, Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano , via Mancinelli 7, I-20131 Milan, Italy.
authors: Pierangelo
authors: P
authors: Metrangolo
authors: NFMLab, Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano , via Mancinelli 7, I-20131 Milan, Italy.
authors: Giuseppe
authors: G
authors: Resnati
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Naomi
authors: N
authors: Sakai
authors: Department of Organic Chemistry, University of Geneva , CH-1211 Geneva, Switzerland.
authors: Stefan
authors: S
authors: Matile
mesh_terms: D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D005466:Fluorocarbons / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011721:Pyrenes / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D005466:Fluorocarbons; D011721:Pyrenes; C030984:pyrene