A novel class of intrinsic proteasome inhibitory gene transfer peptides

Molly E Martin; Kevin G Rice

doi:10.1021/bc700362b

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A novel class of intrinsic proteasome inhibitory gene transfer peptides

Journal article

Peer reviewed

A novel class of intrinsic proteasome inhibitory gene transfer peptides

Molly E Martin and Kevin G Rice

Bioconjugate chemistry, Vol.19(1), pp.370-376

01/2008

DOI: 10.1021/bc700362b

PMCID: PMC3664977

PMID: 18095640

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Abstract

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.

Amino Acid Sequence

Cell Line

Cell Survival - drug effects

Gene Transfer Techniques

Up-Regulation

Esters - metabolism

Leupeptins - pharmacology

DNA - chemistry

Esters - chemistry

Leupeptins - metabolism

Proteasome Endopeptidase Complex - metabolism

Proteasome Inhibitors

Leupeptins - toxicity

Details

Title: Subtitle: A novel class of intrinsic proteasome inhibitory gene transfer peptides
Creators: Molly E Martin - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA
Kevin G Rice
Resource Type: Journal article
Publication Details: Bioconjugate chemistry, Vol.19(1), pp.370-376
DOI: 10.1021/bc700362b
PMID: 18095640
PMCID: PMC3664977
NLM abbreviation: Bioconjug Chem
ISSN: 1043-1802
eISSN: 1520-4812
Publisher: United States
Grant note: DK066212 / NIDDK NIH HHS R01 DK066212 / NIDDK NIH HHS
Language: English
Date published: 01/2008
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Pharmacy Practice and Science; Medicinal and Natural Products Chemistry
Record Identifier: 9984065694502771

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