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    Effects of Tryptophan Content and Backbone Spacing on the Uptake Efficiency of Cell-Penetrating Peptides

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    Type
    Article
    Authors
    Rydberg, Hanna A.
    Matson, Maria
    Åmand, Helene L.
    Esbjörner, Elin K.
    Nordén, Bengt
    Date
    2012-06-28
    Online Publication Date
    2012-06-28
    Print Publication Date
    2012-07-10
    Permanent link to this record
    http://hdl.handle.net/10754/598092
    
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    Abstract
    Cell-penetrating peptides (CPPs) are able to traverse cellular membranes and deliver macromolecular cargo. Uptake occurs through both endocytotic and nonendocytotic pathways, but the molecular requirements for efficient internalization are not fully understood. Here we investigate how the presence of tryptophans and their position within an oligoarginine influence uptake mechanism and efficiency. Flow cytometry and confocal fluorescence imaging are used to estimate uptake efficiency, intracellular distribution and toxicity in Chinese hamster ovarian cells. Further, membrane leakage and lipid membrane affinity are investigated. The peptides contain eight arginine residues and one to four tryptophans, the tryptophans positioned either at the N-terminus, in the middle, or evenly distributed along the amino acid sequence. Our data show that the intracellular distribution varies among peptides with different tryptophan content and backbone spacing. Uptake efficiency is higher for the peptides with four tryptophans in the middle, or evenly distributed along the peptide sequence, than for the peptide with four tryptophans at the N-terminus. All peptides display low cytotoxicity except for the one with four tryptophans at the N-terminus, which was moderately toxic. This finding is consistent with their inability to induce efficient leakage of dye from lipid vesicles. All peptides have comparable affinities for lipid vesicles, showing that lipid binding is not a decisive parameter for uptake. Our results indicate that tryptophan content and backbone spacing can affect both the CPP uptake efficiency and the CPP uptake mechanism. The low cytotoxicity of these peptides and the possibilities of tuning their uptake mechanism are interesting from a therapeutic point of view. © 2012 American Chemical Society.
    Citation
    Rydberg HA, Matson M, Åmand HL, Esbjörner EK, Nordén B (2012) Effects of Tryptophan Content and Backbone Spacing on the Uptake Efficiency of Cell-Penetrating Peptides. Biochemistry 51: 5531–5539. Available: http://dx.doi.org/10.1021/bi300454k.
    Sponsors
    This work was supported by a grant to B.N. from King Abdullah University of Science and Technology (KAUST) and to E.K.E. from the Lennander foundation.
    Publisher
    American Chemical Society (ACS)
    Journal
    Biochemistry
    DOI
    10.1021/bi300454k
    PubMed ID
    22712882
    ae974a485f413a2113503eed53cd6c53
    10.1021/bi300454k
    Scopus Count
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