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Title: Small molecule probes for the elucidation of G-quadruplex function
Author: Shivalingam, Arun
ISNI:       0000 0004 6061 4776
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Mounting evidence suggests that non-canonical nucleic acid structures, termed G-quadruplexes, play functional roles in key biological processes ranging from telomerase dysfunction to gene regulation. As a result, there is also considerable interest in controlling their function to illicit therapeutic effects. However, considerable progress remains to demonstrate their 'drugability'. To this end, a novel optical probe was designed to image G-quadruplex-small molecule interactions in live cells. This compound, DAOTA-M2, displayed enhanced fluorescence lifetimes and amplitudes in the presence of G-quadruplexes with respect to other nucleic acid topologies in vitro, minimal cellular toxicity and favourable nuclear localisation. Live cell imaging studies indicate the compound has the potential to unambiguously image G-quadruplexes. The ability of small molecules to regulate gene expression via G-quadruplex interactions was then explored using a series of metal terpyridine complexes. Attempts to correlate the in vitro G-quadruplex affinity and selectivity of these compounds, with cellular mRNA levels of genes containing functionally characterised G-quadruplexes, failed. No significant trends were observed. Finally, G-quadruplexes in the promoter of MMP2 were characterised as an alternative means of targeting the gene of a protein that so far been 'undrugable'. Two sequences in the MMP2 promoter were shown to from stable G-quadruplexes in vitro. Moreover, reporter gene assays indicate that these G-quadruplexes may play a functional role in cells.
Supervisor: Vilar, Ramon Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral