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A Potent New Class of Reductively Activated Peptide Gene Delivery Agents
Journal article   Open access   Peer reviewed

A Potent New Class of Reductively Activated Peptide Gene Delivery Agents

Donald L. McKenzie, Kai Y. Kwok and Kevin G. Rice
The Journal of biological chemistry, Vol.275(14), pp.9970-9977
04/07/2000
DOI: 10.1074/jbc.275.14.9970
PMID: 10744672
url
https://doi.org/10.1074/jbc.275.14.9970View
Published (Version of record) Open Access

Abstract

A new class of peptide gene delivery agents were developed by inserting multiple cysteine residues into short (dp 20) synthetic peptides. Substitution of one to four cysteine residues for lysine residues in Cys-Trp-Lys18 resulted in low molecular weight DNA condensing peptides that spontaneously oxidize after binding to plasmid DNA to form interpeptide disulfide bonds. The stability of cross-linked peptide DNA condensates increased in proportion to the number of cysteines incorporated into the peptide. Disulfide bond formation led to a decrease in particle size relative to control peptide DNA condensates and prevented dissociation of peptide DNA condensates in concentrated sodium chloride. Cross-linked peptide DNA condensates were 5–60-fold more potent at mediating gene expression in HepG2 and COS 7 cells relative to uncross-linked peptide DNA condensates. The enhanced gene expression was dependent on the number of cysteine residues incorporated, with a peptide containing two cysteines mediating maximal gene expression. Cross-linking peptides caused elevated gene expression without increasing DNA uptake by cells, suggesting a mechanism involving intracellular release of DNA triggered by disulfide bond reduction. The results establish cross-linking peptides as a novel class of potent gene delivery agents that enhance gene expression through a new mechanism of action.

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