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Pawel Guinard

Fighting oxidative stress thanks to NiSOD mimics

Published on 9 October 2023
Thesis presented October 09, 2023

In cells, oxidative stress is defined as the imbalance between reactive oxygen species (ROS) and the quantity of available antioxidant molecules to degrade them. ROS, such as superoxide or hydroxyl radicals, are highly reactive species capable of degrading biological material, leading to the development of pathologies such as inflammatory bowel diseases (IBD) or neurodegenerative diseases. To counteract oxidative stress, living organisms employ efficient antioxidant enzymes known as superoxide dismutases (SODs), which catalyze the dismutation of superoxide into less reactive species: oxygen and hydrogen peroxide. One of these enzymes is the nickel superoxide dismutase (NiSOD), exclusively present in prokaryotes, including certain pathogenic bacteria. Understanding how NiSOD protects these bacteria represents a promising approach for developing antibiotic compounds. Furthermore, the remarkable efficacy of NiSOD has inspired the development of antioxidant compounds for therapeutic applications against oxidative stress-related diseases. Therefore, the objective of this thesis was to create biomimetic complexes inspired by NiSOD's active site to replicate its activity. These complexes are based on a pseudo-ATCUN platform (Amino-Terminal CuII and NiII binding motif), capable of reproducing the NiII geometry in the enzyme's active site. The obtained results have identified two reaction intermediates formed during the dismutation of superoxide by one of these complexes, providing valuable insights into the enzyme mechanism. Additionally, through the identification of factors enhancing SOD activity, highly efficient complexes have been developed, showing potential as antioxidant agents within cells.

NiSOD, oxidative stress, bioinspired mimics, ATCUN, ROS, Ni complexes