Superoxide dismutases (SOD) are very efficient redox metalloproteins, which protect the cell from oxidative stress. Their catalytic activity of superoxide dismutation can be reproduced by low-molecular weight Mn-complexes, called SOD-mimics (SODm) and the overall characteristics of SODs (tuned redox potential, electrostatic guidance of superoxide, compartmentation in organelles) can serve as a guideline in the design of efficient SODm. Oxidative stress, mainly produced in the mitochondria, is involved in inflammation, including Inflammatory Bowel Diseases (IBD), chosen as the biological target. We wish to develop manganese SODm directly inspired from the mitochondrial Mn-SOD that could exert an anti-inflammatory effect through an intracellular antioxidant activity. These will be studied in cellular models of oxidative stress relevant to IBD. This project will involve several steps. First, using a modular approach, we will conjugate a SODm, already developed by the consortium and known to be active in cells, to various vectors and probes to obtain a series of SOD-mimics with tuned cell-penetration properties or organelle targeting, which could be detected inside cells. We will also develop a new series of peptide-based Mn SODm. We will then determine their intrinsic anti-superoxide activity —kinetics of the reaction with superoxide. Their anti-inflammatory effects on several cell models relevant for IBD, intestinal epithelial cells and monocytes/macrophages, will be evaluated by measuring markers of oxidative stress and inflammation and reactive oxygen species (ROS). We will determine the intracellular content in complexes and their sub-cellular location by innovative imaging techniques. What are the main challenges in this project? This project aims at performing inorganic chemistry inside cells and is thus in line with emergent studies dealing with the control and characterization of small metal complexes in cells. This is a very active new field in inorganic chemical biology for which we need to translate the chemical knowledge we have acquired in the chemist’s round-bottom flasks into cells. Enhancing cell penetration and controlling the targeting of SODm to specific organelles is a real challenge, as is the determination of their speciation (or nature) in cells. Physico-chemical techniques to quantify and map metal cations at the sub-cellular level are now emerging: we will apply conventional fluorescence with tagged complexes but also the most recent techniques, such as X-fluorescence for direct sub-cellular mapping of Mn. Success here will certainly lead to a breakthrough in bio-inorganic chemistry as, at present, little information is available on the subcellular distribution of Mn-complexes SODm. This approach will provide guidelines for the rational improvement of antioxidant SODm with an intracellular activity. The project in inorganic biological chemistry dealing with bio-inspired catalytic SOD-mimics design, evaluation and characterization in cells, and sub-cellular imaging will be developed by a consortium with multidisciplinary expertise.