Backbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides

Gisela Lättig-Tünnemann, Manuel Prinz, Daniel Hoffmann, Joachim Behlke, Caroline Palm-Apergi, Ingo Morano, Henry D. Herce () and M. Cristina Cardoso ()
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Gisela Lättig-Tünnemann: Max Delbrueck Center for Molecular Medicine
Manuel Prinz: Center for Medical Biotechnology, University of Duisburg-Essen
Daniel Hoffmann: Center for Medical Biotechnology, University of Duisburg-Essen
Joachim Behlke: Max Delbrueck Center for Molecular Medicine
Caroline Palm-Apergi: Stockholm University
Ingo Morano: Max Delbrueck Center for Molecular Medicine
Henry D. Herce: Technische Universität Darmstadt
M. Cristina Cardoso: Max Delbrueck Center for Molecular Medicine

Nature Communications, 2011, vol. 2, issue 1, 1-6

Abstract: Abstract In addition to endocytosis-mediated cellular uptake, hydrophilic cell-penetrating peptides are able to traverse biological membranes in a non-endocytic mode termed transduction, resulting in immediate bioavailability. Here we analysed structural requirements for the non-endocytic uptake mode of arginine-rich cell-penetrating peptides, by a combination of live-cell microscopy, molecular dynamics simulations and analytical ultracentrifugation. We demonstrate that the transduction efficiency of arginine-rich peptides increases with higher peptide structural rigidity. Consequently, cyclic arginine-rich cell-penetrating peptides showed enhanced cellular uptake kinetics relative to their linear and more flexible counterpart. We propose that guanidinium groups are forced into maximally distant positions by cyclization. This orientation increases membrane contacts leading to enhanced cell penetration.

Date: 2011
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DOI: 10.1038/ncomms1459

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