Activation of Cell-Penetrating Peptides with Ionpair−π Interactions and Fluorophiles

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 o...