TY - JOUR
T1 - The cell-penetrating peptide octa-arginine is a potent inhibitor of proteasome activities
AU - Kloß, Alexander
AU - Henklein, Peter
AU - Siele, Dagmar
AU - Schmolke, Marion
AU - Apcher, Sébastien
AU - Kuehn, Lothar
AU - Sheppard, Paul W.
AU - Dahlmann, Burkhardt
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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.
AB - 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.
KW - Cell-penetrating peptides
KW - HeLa cells
KW - Inhibitor
KW - Octa-arginine
KW - Proteasome
KW - Ubiquitin-conjugated proteins
UR - http://www.scopus.com/inward/record.url?scp=62949248272&partnerID=8YFLogxK
U2 - 10.1016/j.ejpb.2008.10.016
DO - 10.1016/j.ejpb.2008.10.016
M3 - Article
C2 - 19027853
AN - SCOPUS:62949248272
SN - 0939-6411
VL - 72
SP - 219
EP - 225
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
IS - 1
ER -