The cell-penetrating peptide octa-arginine is a potent inhibitor of proteasome activities

Alexander Kloß, Peter Henklein, Dagmar Siele, Marion Schmolke, Sébastien Apcher, Lothar Kuehn, Paul W. Sheppard, Burkhardt Dahlmann

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    43 Citations (Scopus)

    Résumé

    Oligo-arginines are cell-penetrating peptides and find use as carriers for transportation of various membrane-impermeable biopharmaceuticals into target cells. We have found that oligo-arginines of a length of 4-10 amino acids, but especially (Arg)8, are able to inhibit the major intracellular proteolytic system, the proteasome, with mixed-type inhibition characteristics. The IC50 values of (Arg)8 for the proteasomal chymotrypsin-like and caspase-like activities are approximately 100 and 200 nM, respectively. The inhibition of the trypsin-like activity never exceeds 50% even at micromolar concentrations. (Arg)8 also inhibits 20S proteasome/PA28 complexes as well as 26S proteasomes, although with a decreased efficiency. Due to its cell membrane-penetrating capability, incubation of HeLa cells in the presence of (Arg)8 resulted in an impaired activity of proteasomes going along with an accumulation of high-molecular mass ubiquitin-conjugated proteins, the preferred substrates of 26S proteasomes. The in vivo susceptibility of the three proteasome activities resembles that found in vitro with chymotrypsin-like > caspase-like > trypsin-like activities. Since inhibition of the proteasome system might affect fundamental basic cellular processes but on the other side might also prevent the degradation of a proteinacous cargo, we suggest that this proteasome inhibitory activity should be taken into account when oligo-arginines are being considered for use as vectors for the intracellular delivery of pharmaceuticals.

    langue originaleAnglais
    Pages (de - à)219-225
    Nombre de pages7
    journalEuropean Journal of Pharmaceutics and Biopharmaceutics
    Volume72
    Numéro de publication1
    Les DOIs
    étatPublié - 1 mai 2009

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