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Title: Investigating the effect of small molecule ligands and cations on i-motif DNA
Author: Day, Henry
ISNI:       0000 0004 5347 2570
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2015
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The i-motif is an alternative DNA secondary structure motif formed in sequences rich in cytosine, consisting of four strands, stabilised by hemi-protonated cytosine-cytosine+ base pairs. The motif forms in sequences complimentary to the G-quadruplex however, far less is known about the i-motif and most research to date has focused on its application in nanotechnology. Despite this, recent progress in the field has indicated that the i-motif may be a possible therapeutic target in certain cases. In order to study this structure in more detail a chemical tool box of ligands and conditions is needed, which can be used to probe its potential biological function. Herein the effect of small molecule ligands and cations has been investigated. A previously identified i-motif binding compound BisA has been characterised in detail with a range of biophysical experiments, showing that it does bind to the i-motif but causes the DNA to condense. A high throughput screen has been carried out finding a number of potential new i-motif binding ligands and, through a range of experiments, two lead compounds mitoxantrone and tilorone have been identified with micromolar affinities from which novel i-motif binding analogues and structure activity relationships can be developed. Finally, the effect of cations on the i-motif has been studied, including a wider selection from across the periodic table than has previously been investigated. This has shown that at neutral pH, silver (I) ions have the ability to induce i-motif formation and that this is reversible in the presence of cysteine. While at acidic pH, copper (II) ions have the ability to induce hairpin formation reversibly in the presence of EDTA. This could enable the formation of multiple structures from the same oligonucleotide sequence in response to different conditions. The combination of these results should provide useful tools to further study the i-motif structure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available