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Nucleic Acids Research 2004 32(22):6595-6604; doi:10.1093/nar/gkh998
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Published online 15 December 2004

Nucleic Acids Research, Vol. 32 No. 22 © Oxford University Press 2004; all rights reserved

Peptide conjugates for chromosomal gene targeting by triplex-forming oligonucleotides

Faye A. Rogers1,2, Muthiah Manoharan3, Peter Rabinovitch2, David C. Ward2 and Peter M. Glazer1,2,*

1 Department of Therapeutic Radiology and 2 Department of Genetics, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 068520, USA and 3 Isis Pharmaceuticals, Carlsbad, CA, USA

* To whom correspondence should be addressed. Tel: +1 203 737 2787; Fax: +1 203 737 2630; Email: peter.glazer{at}yale.edu

Received September 30, 2004; Revised and Accepted November 24, 2004

Triplex-forming oligonucleotides (TFOs) are DNA-binding molecules, which offer the potential to selectively modulate gene expression. However, the biological activity of TFOs as potential antigene compounds has been limited by cellular uptake. Here, we investigate the effect of cell-penetrating peptides on the biological activity of TFOs as measured in an assay for gene-targeted mutagenesis. Using the transport peptide derived from the third helix of the homeodomain of antennapedia (Antp), we tested TFO–peptide conjugates compared with unmodified TFOs. TFOs covalently linked to Antp resulted in a 20-fold increase in mutation frequency when compared with ‘naked’ oligonucleotides. There was no increase above background in mutation frequency when Antp by itself was added to the cells or when Antp was linked to mixed or scrambled sequence control oligonucleotides. In addition, the TFO–peptide conjugates increased the mutation frequency of the target gene, and not the control gene, in a dose-responsive manner. Confocal microscopy using labeled oligonucleotides indicated increased cellular uptake of TFOs when linked to Antp, consistent with the gene-targeting data. These results suggest that peptide conjugation may enhance intranuclear delivery of reagents designed to bind to chromosomal DNA.


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