Synthesis of DNA binders for tandem repeats of G-quadruplex DNA in telomeric DNA: a target-guided synthetic approach

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

Human telomeric DNA is composed of hundreds of 5'-TTAGGG repeats which end in a single-stranded overhang of around 200 nucleobases. Under physiological conditions, this sequence can fold into a tetra-stranded helical arrangement known as G-quadruplex DNA. This structure has attracted significant attention due to its proposed role in telomere maintenance and consequently its potential as target for the development of new anticancer therapies. Therefore, a large number of small molecules have been developed over the past decade with the aim of selectively binding and stabilising G-quadruplex DNA. While the structures of single G-quadruplexes containing four repeats of the 5'-TTAGGG sequence have been studied in detail, less is known about the higher-order structures formed by longer telomeric sequences. The latter structures, while difficult to study in vitro, are likely to be physiologically more relevant since the single-stranded overhang of telomeric DNA can potentially fold into oligomers containing as many as ten consecutive G-quadruplexes linked by TTA spacers.
In this project, we propose to develop a target-guided synthetic approach to synthesise DNA binders that synergistically bind to two consecutive G4 structures. This approach is likely to yield binders with very high affinity and selectivity for telomeric G4s. This in turn will provide potential new avenues to study the drugability of these sequences.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509486/1 01/10/2016 31/03/2022
1955210 Studentship EP/N509486/1 01/10/2017 31/05/2021 Timothy Kench
 
Description G-Quadruplexes are non-canonical DNA structures which are thought to have an important role in a number of biological processes, including replication, transcription, translation and telomere upkeep. Additionally, they are found in a number of key oncogene promoter regions, making them ideal targets for anti-cancer therapeutics. My project is focused on designing metal complexes which selectively target higher order quadruplexes found at the telomeres as well as complexes which can be activated under certain conditions to improve selective targeting. I have synthesised a number of different compounds which demonstrate this.
Exploitation Route This work provides a foundation for the design of novel metal complexes, including metal complex peptide conjugates, triggerable interlocked molecules and the use of metal complexes as optical probes. Furthermore, more might be able to be discovered about the location of particular higher order G-quadruplex structures.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Imperial Fesival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Helped with running a stand at Imperial Festival/Exhibition Road Festival in which members of the general public could learn about the work carried out in our research group.
Year(s) Of Engagement Activity 2018,2019