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Nucleic Acids Research Advance Access published online on May 27, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp437
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry and Synthetic Biology

High-affinity triplex targeting of double stranded DNA using chemically modified peptide nucleic acid oligomers

Mads E. Hansen, Thomas Bentin and Peter E. Nielsen*

Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200-N, Denmark

*To whom correspondence should be addressed. Tel: +45 35327762/61; Fax: +45 35396042; Email: ptrn{at}sund.ku.dk

Received February 24, 2009. Revised May 8, 2009. Accepted May 11, 2009.

While sequence-selective dsDNA targeting by triplex forming oligonucleotides has been studied extensively, only very little is known about the properties of PNA–dsDNA triplexes—mainly due to the competing invasion process. Here we show that when appropriately modified using pseudoisocytosine substitution, in combination with (oligo)lysine or 9-aminoacridine conjugation, homopyrimidine PNA oligomers bind complementary dsDNA targets via triplex formation with (sub)nanomolar affinities (at pH 7.2, 150 mM Na+). Binding affinity can be modulated more than 1000-fold by changes in pH, PNA oligomer length, PNA net charge and/or by substitution of pseudoisocytosine for cytosine, and conjugation of the DNA intercalator 9-aminoacridine. Furthermore, 9-aminoacridine conjugation also strongly enhanced triplex invasion. Specificity for the fully matched target versus one containing single centrally located mismatches was more than 150-fold. Together the data support the use of homopyrimidine PNAs as efficient and sequence selective tools in triplex targeting strategies under physiological relevant conditions.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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