The cell-penetrating peptide octa-arginine is a potent inhibitor of proteasome activities
| Autor: | Paul W. Sheppard, Marion Schmolke, Alexander Kloss, Dagmar Siele, Peter Henklein, Burkhardt Dahlmann, Sébastien Apcher, Lothar Kuehn |
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| Rok vydání: | 2009 |
| Předmět: |
Proteasome Endopeptidase Complex
Erythrocytes Arginine Chemistry Pharmaceutical Pharmaceutical Science HeLa Ubiquitin Animals Humans Technology Pharmaceutical Muscle Skeletal chemistry.chemical_classification Drug Carriers biology General Medicine biology.organism_classification In vitro Rats Amino acid chemistry Biochemistry Proteasome Drug Design biology.protein Cell-penetrating peptide Peptides Oligopeptides Proteasome Inhibitors Intracellular HeLa Cells Biotechnology |
| Zdroj: | European Journal of Pharmaceutics and Biopharmaceutics. 72:219-225 |
| ISSN: | 0939-6411 |
| DOI: | 10.1016/j.ejpb.2008.10.016 |
| Popis: | 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 IC(50) 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. |
| Databáze: | OpenAIRE |
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