Image: Kollage
Research project financed by the Swedish Research Council.
The structure of DNA as a double helix is well known, less well known is the G-quadruplex DNA structure which has been shown to play central roles in for example gene expression. There are hundreds of thousands of places in the human genome where G-quadruplex DNA structures may form. In this project, we aim to develop a strategy that enable studies of individual G-quadruplex DNA structures, which has direct value on basic research but also great potential from a drug development perspective.
It is well known that our genetic information is stored in our DNA and that it is structured as a double-stranded helix. Less well known is that DNA also can form other types of structures. One example is the G-quadruplex (G4) DNA structure. It is estimated that up to 700,000 G4 DNA structures can form at unique positions in the human genome.
Many of these G4 DNA sequences are evolutionary conserved, suggesting that they have relevant functions. Indeed, G4 DNA structures have been shown to affect a variety of important biological processes (e.g. DNA replication, transcription, and translation) and have been linked to human diseases such as cancer and neurodegenerative disorders. However, there are still large gaps in the knowledge of G4 DNA structures in general, and of individual G4 DNA structures in particular; what are their functions? How are they regulated? Which structures actually forms and when?
To answer these types of questions, we need research tools that bind and stabilize G4 DNA structures. There are today many compounds (some developed in our lab) with ability to bind and stabilize G4 DNA structures. However, most of these compounds stabilize all G4 DNA structures in the genome. To be able to elucidate the role of one particular G4 DNA structure somewhere in the genome, we need a compound that stabilizes only that single G4 DNA structure. With hundreds of thousands of potential G4 DNA structures in the genome, this remains a great challenge.
This project aims to develop compounds that specifically stabilize individual G4 DNA structures using different approaches. We will combine experimental and computational work to understand the details of which factors that govern selective ligand binding and stabilization of G4 DNA and use this in structure-based design approaches to develop drug-like compounds that strongly bind and stabilize specific G4 DNA structures.
