A novel class of intrinsic proteasome inhibitory gene transfer peptides.
Proteasomes are multisubunit enzymes responsible for the degradation of many cytosolic proteins. The inhibition of the proteasome has been the subject of intense interest in the development of drug therapies. We have previously demonstrated that simultaneous administration of a tripeptide aldehyde proteasome inhibitor (MG115 or MG132) with a peptide (Cys-Trp-Lys18) DNA condensate boosted gene expression by 30-fold in cell culture. In the present study, we have developed a convergent synthesis to allow the incorporation of a proteasome inhibitor tripeptide into the C-terminal end of a gene delivery peptide. The resulting peptides formed DNA condensates that mediated a 100-fold enhancement in gene expression over a control peptide lacking all or part of the tripeptide inhibitor. Gene transfer peptides possessing intrinsic proteasome inhibitors were also found to be nontoxic to cells in culture. These results suggest that intrinsic proteasome inhibition may also be used to boost the efficiency of peptide-mediated nonviral gene delivery systems in vivo.
Martin
Molly E
ME
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
Rice
Kevin G
KG
D000595:Amino Acid Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004952:Esters / Q000737:chemistry / Q000378:metabolism; D018014:Gene Transfer Techniques; D007976:Leupeptins / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015854:Up-Regulation
D004952:Esters; D007976:Leupeptins; D061988:Proteasome Inhibitors; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde