Since the identification of DNA as the carrier of genetic information and its key role in the central dogma of molecular biology, numerous applications of nucleic acids, often very different from these original properties, have emerged. It is in regards to the catalytic properties of DNA that this project is focused. Indeed, DNAzymes are molecules able to catalyze various reactions and unlike their RNA counterparts, do not have any precedent in nature. DNAzymes are usually obtained by molecular evolution-based selection techniques which basically aim at achieving Darwinian evolution on a large population of DNA molecules in a test tube. The goals of the projects are to use chemically modified nucleic acids in such selection techniques, in order to unravel DNAzymes that mimic the activity of certain protein enzymes. In particular, using DNA adorned with carboxylic residues could lead to a DNAzyme acting as an artificial aspartic protease, which is able to catalyze the cleavage of amide bonds. Moreover, the use of another modified nucleic acid analog (LNA), known to stabilize DNA duplexes, could lead to the identification of DNAzymes mimicking the enzyme RNase A, which cleaves single stranded RNA strands.
This project could provide significant improvements in the field of catalytic nucleic acids and could have deep ramifications in fundamental research and therapeutical applications. For instance, DNAzymes acting as artificial proteases could be used in the development of new drugs especially towards amyloid diseases such as Alzheimer's disease, while a DNAzyme cleaving RNA linkages could potentially be used as an anti-mRNA agent.
Finally, the project will require a myriad of various techniques ranging from synthetic organic chemistry to the use of molecular biology tools. The combination of these techniques opens up realms of possibilities that could not be reached with only one of these alone.