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Nucleic Acids Research, 2002, Vol. 30, No. 13 2751-2757
© 2002 Oxford University Press

Antisense properties of tricyclo-DNA

Dorte Renneberg, Emilie Bouliong1, Ulrich Reber1, Daniel Schümperli1 and Christian J. Leumann*

1 Departement für Chemie und Biochemie der Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland and 2 Institut für Zellbiologie der Universität Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland

Tricyclo (tc)-DNA belongs to the class of conformationally constrained DNA analogs that show enhanced binding properties to DNA and RNA. We prepared tc-oligonucleotides up to 17 nt in length, and evaluated their binding efficiency and selectivity towards complementary RNA, their biological stability in serum, their RNase H inducing potential and their antisense activity in a cellular assay. Relative to RNA or 2'-O-Me-phosphorothioate (PS)-RNA, fully modified tc-oligodeoxynucleotides, 10–17 nt in length, show enhanced selectivity and enhanced thermal stability by ~1°C/modification in binding to RNA targets. Tricyclodeoxyoligonucleotides are completely stable in heat-deactivated fetal calf serum at 37°C. Moreover, tc-DNA–RNA duplexes are not substrates for RNase H. To test for antisense effects in vivo, we used HeLa cell lines stably expressing the human ß-globin gene with two different point mutations in the second intron. These mutations lead to the inclusion of an aberrant exon in ß-globin mRNA. Lipofectamine-mediated delivery of a 17mer tc-oligodeoxynucleotide complementary to the 3'-cryptic splice site results in correction of aberrant splicing already at nanomolar concentrations with up to 100-fold enhanced efficiency relative to a 2'-O-Me-PS-RNA oligonucleotide of the same length and sequence. In contrast to 2'-O-Me-PS-RNA, tc-DNA shows antisense activity even in the absence of lipofectamine, albeit only at much higher oligonucleotide concentrations.

* To whom correspondence should be addressed. Tel: +41 31 631 4355; Fax: +41 31 631 3422; Email: leumann{at}ioc.unibe.ch


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