Thesis presented September 30, 2019

Abstract:
The superoxide radical anion, O₂^•- , is generated by many life processes. Its radical properties make it a highly reactive species able to damage all macromolecules contributing to the pathogenesis of many diseases including neurodegenerative disorders. In order to protect cells against O₂^•- , Nature uses superoxide dismutases (SODs) which catalyze the dismutation of O₂^•- into hydrogen peroxide and oxygen. The last discovered SOD contains a nickel cofactor. Importantly the NiSOD is found in several pathogenic bacteria but not in humans. Therefore targeting the NiSOD is a promising approach to develop antibiotics. Secondly, the development of novel SOD mimics may have potential uses as therapeutic agents in oxidative stress-related diseases. Our project aims at developing innovative active NiSOD mimics, based on the use of peptide-based ligands with two main objectives: (i) to develop efficient SOD like catalysts, active in water, displaying antioxidant properties for potential therapeutic applications and (ii) to contribute to the full understanding of the catalytic mechanism of the NiSOD to highlight the specific key elements that differentiate NiSOD from the human MnSOD for the design of potential antibiotics. Our results show that, even with a coordination sphere different from the one in the enzyme, a good catalytic activity can be obtained. Key elements for the activity are also determined. Moreover, mechanistic studies indicates an inner sphere mechanism for superoxide reduction.

Keywords:
SOD, superoxide, NiSOD, antibiotics, peptide-based ligands.

On-line thesis.