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Issue 26, 2014
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Interaction of amphiphilic α-helical cell-penetrating peptides with heparan sulfate

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Abstract

Cell-penetrating peptides (CPPs) are able to be taken up by cells and can deliver macromolecular cargos. However, the mechanism of this internalization is not yet fully understood. Recent theories suggest that the binding of cationic CPPs to negatively charged extracellular glycosaminoglycans, such as heparan sulfate (HS), is a possible mechanism of cellular uptake (CU). Our group has screened the CU activities of 54 systematically designed amphiphilic α-helical peptides in HeLa cells. Notably, a mutation in even a single residue significantly alters the CU ability of a peptide. To determine the structure–CU activity relationship of CPPs, four peptides, which contain a difference in one or two amino acids (i.e., Arg/Glu and Ala/Phe), were chosen from our CPP library to examine their interactions with HS. Fluorescence spectroscopy, isothermal titration calorimetry (ITC) and dynamic light scattering analysis indicated that the HS-binding affinities and HS-clustering abilities of the four CPPs correlated well with their CU activities in HeLa and A549 cells. The heat capacities of the CPPs, determined using ITC and binding free energy decomposition analyses in molecular dynamics simulations, revealed that electrostatic interactions were more dominant in the HS-binding processes of Arg-containing peptides in comparison to Glu-containing peptides, whereas hydrophobic contributions were the primary mode of interaction of Phe-containing peptides in comparison to Ala-containing peptides. Furthermore, it was implied that hydrophobic interactions may be more favourable than electrostatic interactions during the CU process.

Graphical abstract: Interaction of amphiphilic α-helical cell-penetrating peptides with heparan sulfate

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Publication details

The article was received on 31 Mar 2014, accepted on 14 Apr 2014 and first published on 15 Apr 2014


Article type: Paper
DOI: 10.1039/C4OB00673A
Citation: Org. Biomol. Chem., 2014,12, 4673-4681
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    Interaction of amphiphilic α-helical cell-penetrating peptides with heparan sulfate

    J. Yang, H. Tsutsumi, T. Furuta, M. Sakurai and H. Mihara, Org. Biomol. Chem., 2014, 12, 4673
    DOI: 10.1039/C4OB00673A

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