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J. Biol. Chem., Vol. 280, Issue 20, 20076-20085, May 20, 2005

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Exploring Cellular Activity of Locked Nucleic Acid-modified Triplex-forming Oligonucleotides and Defining Its Molecular Basis^*

Erika Brunet, Patrizia Alberti, Loïc Perrouault, Ravindra Babu¶, Jesper Wengel¶, and Carine Giovannangeli||

From the Laboratoire de Biophysique, Museum National d'Histoire Naturelle USM 503, CNRS UMR 5153, INSERM U 565, 43 rue Cuvier, 75005 Paris, France and ^¶Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark

Triplex-forming oligonucleotides (TFOs), as DNA-binding molecules that recognize specific sequences, offer unique potential for the understanding of processes occurring on DNA and associated functions. They are also powerful DNA recognition elements for the positioning of ubiquitous molecules acting on DNA, such as anticancer drugs. A prerequisite for further development of DNA code-reading molecules including TFOs is their ability to form a complex in a cellular context: their binding affinities must be comparable to those of DNA-associated proteins. To reach this goal, chemically modified TFOs must be developed. In this work, we present triplex-forming properties (kinetics and thermodynamics) and cellular activity of G-containing locked nucleic acid-modified TFOs (TFO/LNAs). In conditions simulating physiological ones, these TFO/LNAs strongly enhanced triplex stability compared with the non-modified TFO or with the pyrimidine TFO/LNA directed against the same oligopyrimidine·oligopurine sequence, mainly by decreasing the dissociation rate constant and conferring an entropic gain. We provide evidence of their biological activity by a triplex-based mechanism, in vitro and in a cellular context, under conditions in which the parent phosphodiester oligonucleotide did not exhibit any inhibitory effect.

Received for publication, January 2, 2005 , and in revised form, March 2, 2005.

^* This work was supported in part by grants from La Ligue Nationale Contre le Cancer and by The Danish National Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the French Ministry for Research.

^|| To whom correspondence should be addressed. E-mail: giovanna{at}mnhn.fr.

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