Maurice Michel

1. Development of OGG1 activators

In June 2022, we were first to report cellularly active organocatalysts – organocatalytic switches, we call them ORCAs, assist the enzyme in reaction turnover and diversification of substrate and product scope. Based on some of the findings, we continue to drive synthetic chemistry with help of X-Ray co-crystal structures and computational chemistry. Our goals within this context, are the exact control of product scope, the tuning of a defined pH range of OGG1 biochemical reactions and the selective targeting of cellular organelles. With this achieved for lead molecules, we recruit or collaborate with disease experts to reach proof of principle in disease models driven by OGG1 biology or oxidative stress to the genome in general. We also aim to understand the activation of elimination mechanisms in DNA repair by exploiting chemical principles, such as leaving group activation, proton abstraction and aldehyde tuning. Here, we are making great strides in reducing the necessary molecularity, dramatically increasing enzyme turnover.

2. Broadening of the technology base of enzyme activation

Although OGG1 is no significant AP-lyase in cells, DNA glycosylases with pronounced β- or β, δ-AP lyase activity exist in humans and other species. Understanding how these activities are controlled on a molecular level, allows us to alter enzyme function at will and thus generate new DNA repair pathways for the treatment of disease. We call this strategy chemical switching. Along these lines, we have designed bioinformatics workflows that allow us to identify enzymes suitable for artificial functions. We then perform computational calculations to elucidate chemical and biochemical reaction mechanisms, generate amino acid mutants, develop ORCAs and engineer proteins through amino acid selective modifications and bioorthogonal chemistry. The ultimate goal: enabling an array of enzymes to cleave non-natural substrates through previously unreported reaction pathways. To achieve this, we leverage our expertise in computational chem/bioinformatics, the design of bio-macromolecules, gain-of-function enzymes and additional ORCAs. Once a technology is established in vitro, we characterize the consequences of chemical switching in a cellular context. As of now, we employ techniques from DNA repair to quantify the altered physiological state of a several enzymes. Developing the platform further, we will move from DNA repair to other metabolic pathways. Importantly, the implications of this research reach also beyond medicine and thus we also collaborate with industry partners to impact biocatalysis.

3. A Nordic DNA glycosylase platform

Eleven human DNA glycosylases exist and most of them are considered understudied. In extension of the EUbOPEN consortium and the SGC, we have joined forces with partners in Sweden and Norway to assemble all of them physically. We have developed a platform that includes in vitro and cellular assays for selectivity/activity readout and target engagement. In collaboration with partners at the SGC and Target 2035 we perform large scale screens, solve crystal structures, generate selective antibodies and other reagents and enable investigation of the entire protein family – effectively deorphanizing them for investigation. We donate this setup to the scientific community through protocols within EUbOPEN and Target2035. Ultimately, we thrive to combine our work on ORCAs with these novel targets and enable the studying of DNA repair biology.

We are deeply committed to mentoring, coaching, teaching and supporting the next generation of students. Our strategic exchange program with the Universities of St. Andrews and Edinburgh has led to fruitful collaborations and a uniquely educated generation of undergraduate students – their success is our legacy. In addition, we teach in the Biomedicine program across the entire curriculum. Reach out, if you want to work with us and shape the future in protein regulation.