Gas-phase fragmentation and conformation of the sugar-modified antisense oligonucleotide tcDNA

Hari, Yvonne; Schürch, Stefan (29 October 2015). Gas-phase fragmentation and conformation of the sugar-modified antisense oligonucleotide tcDNA (Unpublished). In: Meeting of the Swiss Group for Mass Spectrometry. Beatenberg. 29.10.2015.

Official URL: http://www.sgms.ch

Tricyclo-DNA (tcDNA) is a sugar- and backbone-modified analogue of DNA that is currently tested as antisense oligonucleotide for the treatment of Duchenne muscular dystrophy. The name tricyclo-DNA is derived from the modified sugar-moiety: the deoxyribose is extended to a three-membered ring system. This modification is designed to limit the flexibility of the structure, thus giving rise to entropically stabilized hybrid duplexes formed between tcDNA and complementary DNA or RNA oligonucleotides. While the structural modifications increase the biostability of the therapeutic agent, they also render the oligonucleotide inaccessible to enzyme-based sequencing methods. Tandem mass spectrometry constitutes an alternative sequencing technique for partially and fully modified oligonucleotides. For reliable sequencing, the fragmentation mechanism of the structure in question must be understood. Therefore, the presented work evaluates the effect of the modified sugar-moiety on the gas-phase dissociation of single stranded tcDNA. Moreover, our experiments reflect the exceptional gas-phase stability of hybrid duplexes that is most noticeable in the formation of truncated duplex ions upon collision-induced dissociation. The stability of the duplex arises from the modified sugar-moiety, as the rigid structure of the tcDNA single strand minimizes the change of the entropy for the annealing. Moreover, the tc-modification gives rise to extended conformations of the nucleic acids in the gas-phase, which was studied by ion mobility spectrometry-mass spectrometry.

Item Type:

Conference or Workshop Item (Speech)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Hari, Yvonne and Schürch, Stefan

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

Language:

English

Submitter:

Stefan Schürch

Date Deposited:

02 Feb 2016 16:19

Last Modified:

02 Feb 2016 16:19

URI:

https://boris.unibe.ch/id/eprint/75107

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