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Title: Synthesis and properties of nucleic acid analogues containing artificial backbones
Author: Tyburn, Agnes
ISNI:       0000 0004 7654 6325
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Nucleic acid analogues are very attractive molecules for therapeutic applications as in principle they can specifically inhibit the expression of virtually any gene through antisense or RNA interference pathways. For this purpose, nucleic acid analogues with modified backbones have advantageous properties compared to their natural counterparts. In particular they can provide better resistance to nucleases as well as improving cellular uptake. However, radically changing the nucleic acid backbone while maintaining a good affinity for a mRNA or DNA target remains challenging. Developing synthetic strategies to conveniently access new modified backbones that could be used in antisense oligonucleotides is therefore essential. With this in mind a new solid-phase method to efficiently functionalise an amine-modified DNA backbone has been developed. Using this approach, three new oligonucleotide modified backbones have been synthesised, and their hybridisation properties have been investigated. Modified DNA backbones are also potentially useful in the development of new methods for chemical-ligation of oligonucleotides. This approach could allow the large-scale de novo synthesis of genes containing site-specific chemical modifications including epigenetic signals. Such constructs represent challenging targets in medicinal and biotechnology applications. An important class of modified DNA linkages containing a triazole ring developed in our research group has been further investigated through the synthesis of two new triazole modified backbones. The synthesis of a DNA amide backbone with favourable duplex stability was also performed. A detailed study of the biophysical properties of the above modified backbones including their performance as templates for various DNA polymerases has been carried out.
Supervisor: Brown, Tom Sponsor: ATDbio
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Nucleic acids