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

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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.