Peptide-based metal complexes mimicking metalloenzymes activity – MetalloPepZyme

Catalases (CAT) and superoxide dismutases (SOD) are antioxidant metalloenzymes necessary for life in oxygen-metabolizing cells to regulate reactive oxygen species (ROS) levels. CAT and SOD take advantages of the redox properties of the metal ion involved in their active site to accelerate the conversion of hydrogen peroxide and the dismutation of superoxide radical, respectively. Many physio-pathological situations are associated with oxidative stress during which these antioxidant defenses are overwhelmed. In the line of the emerging field of catalytic drugs, we propose to develop new bioinspired peptide-based metal complexes mimicking SOD and CAT activities. Towards this goal, the complexes will be selected among a combinatorial library synthesized on solid support via an activity assay in gel. This will allow finding rapidly efficient complexes for the desired enzyme activity. In order to improve the stability of the complexes, the selective pressure will be increased by performing the gel assays in presence of competitive ligands and / or in presence of proteases. After the selection step, the winning complexes will be evaluated in vitro for their catalytic activity and stability. They will be then assayed in cells for their antioxidant properties in a cellular model of inflammation mediated by ROS. This evaluation will rely on the measurement of inflammation markers such as Interleukine 8 (IL8), as well as antioxidant enzymes expression (SOD, CAT…) and ROS quantification. If the complexes do not penetrate the cells in a sufficient amount or if the intracellular localization is not well adapted, thanks to the versatility of peptide chemistry, it will be possible to add cell penetrating or organelle targeting sequences to the peptidic ligand.