Eppendorf Award for Young European Investigators 2023

The award is given to Dr. Maurice Michel (Science for Life, Karolinka Institute, Stockholm, Sweden). Maurice studied chemistry at the Clausthal University of Technology (B.Sc., M.Sc.). Moving to the Max Planck Institute of Colloids and Interfaces and Freie Universität Berlin, he worked on his doctorate under Peter Seeberger and Daniel Varón Silva, focusing on carbohydrate antigens of Trypanosoma brucei. He then pursued postdoctoral studies at Science for Life Laboratory and Karolinska Institutet in Stockholm to investigate DNA glycosylases with Thomas Helleday. There, a site project on synthetic activators led him to pioneering the control of artificial enzymatic functions in the DNA glycosylase OGG1. Currently, his research focuses on establishing this technology for additional enzymes and the understanding of biochemical and biological consequences of reprogrammed DNA repair.

Oxidative DNA damage may be both cause and consequence of a number of human diseases, among them inflammation, cancer, neurodegenerative diseases and others. To maintain DNA damage at an acceptable level, several DNA repair pathways with a significant number of enzymes have evolved during evolution. 8-oxo Guanine (8-oxoG) is the most common product of oxidation in DNA and is removed by the 8-oxo Guanine DNA glycosylase 1 (OGG1). OGG1 removes 8-oxoG from DNA and forms a reversible but long-lasting bond with the remaining DNA strand. Interestingly, oxidative conditions within the cell will prolong the time, that OGG1 remains bound in this intermediate state. Within the different DNA repair pathways, only few proteins exist, that can stimulate OGG1 to cleave the bond to the DNA strand. Thus, processes such as inflammation, cancer and even working out will delay this cleavage of DNA through the generation of oxidative DNA damage.

Since the discovery of DNA glycosylases DNA repair has experienced a significant push and the mechanisms of partaking enzymes have been elucidated. In addition, within the last two decades, organocatalysts have emerged as a powerful technology to mimic enzymatic functions using only small organic molecules. Traditionally, a union of enzymatic and organocatalytic function has been considered unattractive, since participating in enzymatic functions requires the small molecule to bind close to the substrate site, effectively generating a classic inhibitor. We have recently demonstrated, that this limitation can be overcome for the unproductive complex of OGG1 and bound DNA. For the first time in scientific literature, we showed that a small molecule that binds the active site of an enzyme can increase the enzymes activity in cells. We rationalized and synthesized compounds to control OGG1 cleavage from DNA though a nitrogen base within their molecular structures. Several series of molecules were developed and enable to rationally generate different DNA repair products, altering how the cell deals with DNA damage. This mode of action equals a molecular switch and opens exciting opportunities in diseases characterized by oxidative DNA damage.