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Conférence : « Peptides as tools to understand Copper homeostasis and treat Wilson Disease. »
Abstract :
Proteins involved in copper homeostasis are outstanding sources of inspiration for the design of efficient CuI chelators. In metallochaperones, CuI is mainly bound by soft donors like cysteine thiolates. This has led us to design peptides including two cysteines, which show an affinity for CuI similar to that of the metallochaperones (Kd~10-16) and a high selectivity over ZnII, another essential metal ion found in cells. Even more efficient CuI chelators were obtained by favoring a CuS3 coordination environment in mononuclear and cluster-type complexes, as found in metallothioneins (MT). Three cysteine residues were attached with peptide bonds to non biological scaffolds to get pseudopeptide ligands which demonstrate a very high affinity for CuI similar to that of MT (Kd~10-19).
The complexation properties of these novel bioinspired chelating molecules will be presented. Two of them have also been functionalized by specific ligands of receptors located at the liver’s surface to obtain glycojugates, which have been demonstrated to chelate intracellular copper in hepatocytes. Therefore, these glycoconjugates are promising candidates to fight against copper overload in the liver in Wilson’s disease patients.[:]