Activation
of Cell-Penetrating Peptides with Ionpair−π
Interactions and Fluorophiles
Version 2 2016-08-31, 13:01
Version 1 2016-08-26, 21:17
Posted on 2016-08-29 - 00:00
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.
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Chuard, Nicolas; Fujisawa, Kaori; Morelli, Paola; Saarbach, Jacques; Winssinger, Nicolas; Metrangolo, Pierangelo; et al. (2016). Activation
of Cell-Penetrating Peptides with Ionpair−π
Interactions and Fluorophiles. ACS Publications. Collection. https://doi.org/10.1021/jacs.6b06253
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AUTHORS (9)
NC
Nicolas Chuard
KF
Kaori Fujisawa
PM
Paola Morelli
JS
Jacques Saarbach
NW
Nicolas Winssinger
PM
Pierangelo Metrangolo
GR
Giuseppe Resnati
NS
Naomi Sakai
SM
Stefan Matile