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Published online 29 March 2004

Nucleic Acids Research, 2004, Vol. 32, No. 6 1874-1885
© 2004 Oxford University Press

Transcription factor decoy oligonucleotides modified with locked nucleic acids: an in vitro study to reconcile biostability with binding affinity

Rita Crinelli, Marzia Bianchi, Lucia Gentilini, Linda Palma, Mads D. Sørensen1, Torsten Bryld1, Ravindra B. Babu1, Khalil Arar2, Jesper Wengel1 and Mauro Magnani*

Istituto di Chimica Biologica ‘G. Fornaini’, Università degli Studi di Urbino ‘Carlo Bo’, Via Saffi 2, I-61029 Urbino, Italy, 1 Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, DK-5230 Odense M, Denmark and 2 Proligo LLC, 1 Rue Delaunay, 75011 Paris, France

*To whom correspondence should be addressed. Tel: +39 0722 305211; Fax: +39 0722 320188; Email: magnani{at}uniurb.it

Received January 26, 2004; Revised and Accepted March 4, 2004

Double-stranded oligonucleotides (ODNs) containing the consensus binding sequence of a transcription factor provide a rationally designed tool to manipulate gene expression at the transcriptional level by the decoy approach. However, modifications introduced into oligonucleotides to increase stability quite often do not guarantee that transcription factor affinity and/or specificity of recognition are retained. We have previously evaluated the use of locked nucleic acids (LNA) in the design of decoy molecules for the transcription factor {kappa}B. Oligo nucleotides containing LNA substitutions displayed high resistance to exo- and endonucleolytic degradation, with LNA–DNA mix-mers being more stable than LNA–DNA–LNA gap-mers. However, insertion of internal LNA bases resulted in a loss of affinity for the transcription factor. This latter effect apparently depended on positioning of the internal LNA substitutions. Indeed, here we demonstrate that intra- and inter-strand positioning of internal LNAs has to be carefully considered to maintain affinity and achieve high stability, respectively. Unfortun ately, our data also indicate that LNA positioning is not the only parameter affecting transcription factor binding, the interference in part being dependent on the intrinsic conformational properties of this nucleotide analog. To circumvent this problem, the successful use of an {alpha}-L-ribo- configured LNA is demonstrated, indicating LNA–DNA–{alpha}-L-LNA molecules as promising new decoy agents.


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