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: 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.
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.
Organisations
People |
ORCID iD |
Ramon Vilar Compte (Primary Supervisor) | |
Timothy Kench (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509486/1 | 30/09/2016 | 30/03/2022 | |||
1955210 | Studentship | EP/N509486/1 | 30/09/2017 | 29/04/2021 | 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 |