Hari, Yvonne; Leumann, Christian; Schürch, Stefan (15 September 2016). Gas-phase properties of natural and modified nucleic acid duplexes. CHIMIA, 70(7/8). Schweizerische Chemische Gesellschaft
Antisense therapy aims at treating hereditary diseases by modifying the processing of mRNAs, for instance by inducing alternative splicing. For most effective treatment at minimal dose, the antisense oligonucleotides should selectively bind the targeted mRNA and evade fast enzymatic degradation. These properties are introduced by structural modifications in the synthetic oligonucleotide. One promising example of antisense chemistries is tricyclo-DNA (tcDNA), a DNA analogue comprising a three-membered ring system instead of the deoxyribose moiety.
The relative stability of natural and modified nucleic acid duplexes can be assessed by tandem mass spectrometric experiments. On one hand, these experiments probe the specificity of antisense oligonucleotides for their designated target and provide insight into the interaction between complementary strands. On the other hand, comparison of different types of nucleic acid duplexes illustrates the contribution of thermodynamic parameters to the gas-phase stability of duplexes. The entropy-favored strand separation is the dominant fragmentation channel in DNA duplexes. In modified heteroduplexes, by contrast, alternative reaction pathways compete with strand separation because the free activation enthalpies of the different channels converge.
The conformation and rigidity of higher-order nucleic acid structures were probed by ion-mobility spectrometry-mass spectrometry (IMS-MS). It was found that the modified sugar-moiety leads to a substantial increase of the collision cross-section in single strands and duplexes. Presumably, tcDNA adopts an extended conformation because the rigid sugar-moiety restricts the contraction of the molecule to a more compact, globular structure. Moreover, ion-mobility experiments evidence how the charge state influences the extension of the macromolecule as well as the rigidity of the structure.
Item Type: |
Conference or Workshop Item (Poster) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Hari, Yvonne Ilona, Leumann, Christian, Schürch, Stefan |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry 500 Science |
ISSN: |
0009-4293 |
Publisher: |
Schweizerische Chemische Gesellschaft |
Language: |
English |
Submitter: |
Stefan Schürch |
Date Deposited: |
23 Sep 2016 14:55 |
Last Modified: |
02 Mar 2023 23:28 |
URI: |
https://boris.unibe.ch/id/eprint/88525 |
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