Korotkovs, Valerijs (2019) Molecular construction of sulfonamide oligonucleotides. PhD thesis, University of Glasgow.
Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.Abstract
Antisense oligonucleotides (ASO's) are a class of therapeutics that target RNA. Advancements in chemical modifications of oligonucleotides culminated in recent FDA approvals of three ASO's for the treatment of homozygous familial hypercholesterolemia (Kynamro), Duchenne muscular dystrophy (Eteplirsen), and spinal muscular atrophy (Spinraza). In this work, efforts towards an efficient and scalable synthesis of sulfonamide oligonucleotide monomers were developed for replacement of the phosphodiester linker of RNA by a sulfonamide-containing linker to allow construction of sulfonamide oligonucleotides. The synthesis of monomers is described through Chapters 2 to 4. Using the described monomers, it was possible to synthesise sulfonamide oligonucleotides in solution phase and some crucial properties of the resulting oligonucleotides like cell permeability were studied in Chapter 5.A sulfonamide-phosphodiester oligonucleotide chimera (SaDNA) was prepared by synthesising a sulfonamide Thymine-Thymine dimer compatible with phosphoramidite chemistry and incorporating it into a DNA sequence in Chapter 6. The resulting SaDNA was used in a thermal stability experiment to study SaRNA double-strand complexes with DNA and RNA. Although sulfonamide modification caused a decrease in melting temperature (Tm) the incorporated sulfonamide monomer displayed selectivity in binding to RNA. A preliminary experiment was performed using the prepared sulfonamide monomers to synthesise oligonucleotides on solid phase using a Rink amide-polystyrene resin in Chapter 7.
| Item Type: | Thesis (PhD) |
|---|---|
| Qualification Level: | Doctoral |
| Subjects: | Q Science > QD Chemistry |
| Colleges/Schools: | College of Science and Engineering > School of Chemistry |
| Supervisor's Name: | Liskamp, Prof. Robert |
| Date of Award: | 2019 |
| Embargo Date: | 31 September 2020 |
| Depositing User: | Mr Valerijs Korotkovs |
| Unique ID: | glathesis:2019-76742 |
| Copyright: | Copyright of this thesis is held by the author. |
| Date Deposited: | 10 Dec 2019 13:40 |
| Last Modified: | 05 Mar 2020 21:56 |
| Thesis DOI: | 10.5525/gla.thesis.76742 |
| URI: | http://theses.gla.ac.uk/id/eprint/76742 |
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