Specificity – the key to explore G-quadruplex DNA

There are hundreds of thousands of guanine rich sequences in the human genome with potential to form G-quadruplex DNA structures (G4s).

Lately, G4s have been linked to key cellular processes such as gene regulation as well as human diseases such as cancer. However, there are still large gaps in the knowledge of G4 biology. The main reason for this is the lack of methods to study individual G4s.

To elucidate the role (or therapeutic potential) of one particular G4, we need a compound that stabilizes only that single G4 – a great challenge considering the plethora of potential G4s.

This proposal presents strategies to generate compounds with ability to bind and stabilize individual G4s using a structure-based design strategy and a novel approach where an oligonucleotide recognition sequence is linked to a G4 stabilizing compound.

The project is highly interdisciplinary and built around design-make-test cycles (computational studies based on structural biology, organic/medicinal chemistry, and biophysical/biochemical assays) to develop the strategies.

Promising compounds will be applied to study certain G4s, the biological processes they effect, and their therapeutic potential together with collaborators.

If successful, the strategy will be a huge breakthrough in the research field of G4s with potential to open doors to untapped scientific ground in many directions. Furthermore, the presented strategy also opens the possibility to explore an array of novel therapeutic targets.