Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.808151
Title: (E)-Vinylphosphonates : nuclease-stable phosphate mimics for effective single-stranded RNA gene silencing
Author: Al-Kadhimi, Mustafa M.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2020
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Abstract:
The therapeutic efficacy of double-stranded short interfering RNAs (ds-siRNAs) is limited by the formation of the lipid complex to deliver them to cells. Whereas if effective single-stranded siRNAs (ss-siRNAs) could be developed, they would offer an easier way of delivery and they can be produced at half price. Chemical modifications to ss-siRNAs are required to improve gene-silencing efficacy in vivo and to enhance their nuclease stability. This study describes a synthetic route that can access all the possible combinations of the modified (E)-vinylphosphonate ((E)-VP) linked-dinucleotides. Additionally, it demonstrates a method to synthesise a ss-siRNA contain a single 5′-terminus (E)-vinyphosphonate (5′-(E)-VP) using the standard phosphoramidite method that does not require additional deprotection steps. The study shows that the vinylphosphonate is well tolerated in the 5′-terminus between nucleotide 1 and nucleotide 2 of the ss-siRNA, and that shown efficient in vitro and in vivo knockdown of luciferase in MDA-MB fluc cells in comparison to a negative control. This study shows that (E)-VP linked-dinucleotides can also be incorporated in the 3′-terminus of the oligonucleotide, this can extend the study to investigate the effect of the presence of multiple vinylphosphonates on the overall stability and activity of the oligonucleotide. Furthermore, the study describes a synthetic method to synthesise dinucleotide and trinucleotide that have two and three consecutive 5′-(E)-VP but can only be used in the 5′-termius of the oligonucleotide. Finally, this thesis will suggest a synthetic route to synthesise consecutive vinylphosphonates that possibly can be used at any position of the oligonucleotide.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.808151  DOI: Not available
Keywords: QD415 Biochemistry
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