TY - JOUR

T1 - Membrane adsorption and binding, cellular uptake and cytotoxicity of cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone

T2 - effects of hydrogen bonding and α-chirality in the β-peptoid residues

AU - Jing, Xiaona

AU - Yang, Mingjun

AU - Kasimova, Marina Robertovna

AU - Malmsten, Martin

AU - Franzyk, Henrik

AU - Jørgensen, Lene

AU - Foged, Camilla

AU - Nielsen, Hanne Mørck

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2012

Y1 - 2012

N2 - Cell-penetrating peptides (CPPs) provide a promising approach for enhancing intracellular delivery of therapeutic biomacromolecules by increasing transport through membrane barriers. Here, proteolytically stable cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone were studied to evaluate the effect of α-chirality in the β-peptoid residues and the presence of guanidinium groups in the α-amino acid residues on membrane interaction. The molecular properties of the peptidomimetics in solution (surface and intramolecular hydrogen bonding, aqueous diffusion rate and molecular size) were studied along with their adsorption to lipid bilayers, cellular uptake, and toxicity. The surface hydrogen bonding ability of the peptidomimetics reflected their adsorbed amounts onto lipid bilayers as well as with their cellular uptake, indicating the importance of hydrogen bonding for their membrane interaction and cellular uptake. Ellipsometry studies further demonstrated that the presence of chiral centers in the β-peptoid residues promotes a higher adsorption to anionic lipid bilayers, whereas circular dichroism results showed that α-chirality influences their overall mean residue ellipticity. The presence of guanidinium groups and α-chiral β-peptoid residues was also found to have a significant positive effect on uptake in living cells. Together, the findings provide an improved understanding on the behavior of cell-penetrating peptidomimetics in the presence of lipid bilayers and live cells.

AB - Cell-penetrating peptides (CPPs) provide a promising approach for enhancing intracellular delivery of therapeutic biomacromolecules by increasing transport through membrane barriers. Here, proteolytically stable cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone were studied to evaluate the effect of α-chirality in the β-peptoid residues and the presence of guanidinium groups in the α-amino acid residues on membrane interaction. The molecular properties of the peptidomimetics in solution (surface and intramolecular hydrogen bonding, aqueous diffusion rate and molecular size) were studied along with their adsorption to lipid bilayers, cellular uptake, and toxicity. The surface hydrogen bonding ability of the peptidomimetics reflected their adsorbed amounts onto lipid bilayers as well as with their cellular uptake, indicating the importance of hydrogen bonding for their membrane interaction and cellular uptake. Ellipsometry studies further demonstrated that the presence of chiral centers in the β-peptoid residues promotes a higher adsorption to anionic lipid bilayers, whereas circular dichroism results showed that α-chirality influences their overall mean residue ellipticity. The presence of guanidinium groups and α-chiral β-peptoid residues was also found to have a significant positive effect on uptake in living cells. Together, the findings provide an improved understanding on the behavior of cell-penetrating peptidomimetics in the presence of lipid bilayers and live cells.

KW - Adsorption

KW - Calorimetry

KW - Circular Dichroism

KW - HeLa Cells

KW - Humans

KW - Hydrogen Bonding

KW - Liposomes

KW - Models, Molecular

KW - Molecular Dynamics Simulation

KW - Peptidomimetics

KW - Peptoids

KW - Protein Binding

KW - Stereoisomerism

U2 - 10.1016/j.bbamem.2012.05.003

DO - 10.1016/j.bbamem.2012.05.003

M3 - Journal article

C2 - 22609348

VL - 1818

SP - 2660

EP - 2668

JO - B B A - General Subjects

JF - B B A - General Subjects

SN - 0304-4165

IS - 11

ER -