Membrane adsorption and binding, cellular uptake and cytotoxicity of cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone: effects of hydrogen bonding and α-chirality in the β-peptoid residues

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Xiaona Jing, Mingjun Yang, Marina Robertovna Kasimova, Martin Malmsten, Henrik Franzyk, Lene Jørgensen, Camilla Foged, Hanne Mørck Nielsen

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.
Original languageEnglish
JournalBBA General Subjects
Volume1818
Issue number11
Pages (from-to)2660-2668
Number of pages9
ISSN0304-4165
DOIs
Publication statusPublished - 2012

    Research areas

  • Adsorption, Calorimetry, Circular Dichroism, HeLa Cells, Humans, Hydrogen Bonding, Liposomes, Models, Molecular, Molecular Dynamics Simulation, Peptidomimetics, Peptoids, Protein Binding, Stereoisomerism

ID: 104572616