title: Backbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides.
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.
authors: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors: Gisela
authors: G
authors: Lättig-Tünnemann
authors: Manuel
authors: M
authors: Prinz
authors: Daniel
authors: D
authors: Hoffmann
authors: Joachim
authors: J
authors: Behlke
authors: Caroline
authors: C
authors: Palm-Apergi
authors: Ingo
authors: I
authors: Morano
authors: Henry D
authors: HD
authors: Herce
authors: M Cristina
authors: MC
authors: Cardoso
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D002477:Cells / Q000737:chemistry / Q000378:metabolism*; D019791:Guanidine / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure
chemical_list: D057846:Cell-Penetrating Peptides; D001120:Arginine; D019791:Guanidine