Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes

Ittig, Damian; Gerber, Anna-Barbara; Leumann, Christian J. (2011). Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes. Nucleic acids research, 39(1), pp. 373-380. London: Oxford University Press 10.1093/nar/gkq733

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A series of oligodeoxyribonucleotides and oligoribonucleotides containing single and multiple tricyclo(tc)-nucleosides in various arrangements were prepared and the thermal and thermodynamic transition profiles of duplexes with complementary DNA and RNA evaluated. Tc-residues aligned in a non-continuous fashion in an RNA strand significantly decrease affinity to complementary RNA and DNA, mostly as a consequence of a loss of pairing enthalpy DeltaH. Arranging the tc-residues in a continuous fashion rescues T(m) and leads to higher DNA and RNA affinity. Substitution of oligodeoxyribonucleotides in the same way causes much less differences in T(m) when paired to complementary DNA and leads to substantial increases in T(m) when paired to complementary RNA. CD-spectroscopic investigations in combination with molecular dynamics simulations of duplexes with single modifications show that tc-residues in the RNA backbone distinctly influence the conformation of the neighboring nucleotides forcing them into higher energy conformations, while tc-residues in the DNA backbone seem to have negligible influence on the nearest neighbor conformations. These results rationalize the observed affinity differences and are of relevance for the design of tc-DNA containing oligonucleotides for applications in antisense or RNAi therapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Ittig, Damian; Gerber, Anna-Barbara and Leumann, Christian

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0305-1048

Publisher:

Oxford University Press

Language:

English

Submitter:

Christian Leumann

Date Deposited:

04 Oct 2013 14:26

Last Modified:

26 Oct 2019 16:35

Publisher DOI:

10.1093/nar/gkq733

Web of Science ID:

000286008500036

BORIS DOI:

10.7892/boris.9413

URI:

https://boris.unibe.ch/id/eprint/9413 (FactScience: 215145)

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