title: Design of intrahepatocyte copper(I) chelators as drug candidates for Wilson's disease.
abstract: Wilson's disease is an autosomal recessive disease caused by mutations on the ATP7B gene found on chromosome 13. Since the corresponding ATPase is in charge of copper (Cu) distribution and excretion in the liver, its malfunctioning leads to Cu overload. This short review deals with treatments of this rare disease, which aim at decreasing Cu toxicity and are, therefore, based on chelation therapy. The drugs used since the 1950s are described first, then a novel approach developed in our laboratory is presented. Since the liver is the main organ of Cu distribution in the body, we targeted the pool of intracellular Cu in hepatocytes. This Cu pool is in the +1 oxidation state, and therefore soft sulfur ligands inspired from binding sites found in metallothioneins were developed. Their targeting to the hepatocytes by functionalization with ligands of the asialoglycoprotein receptor led to their cellular incorporation and intracellular Cu chelation.
authors.affiliation: Laboratoire Reconnaissance Ionique et Chimie de Coordination, Université Joseph Fourier-Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, Grenoble, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Gateau
authors.forename: Pascale
authors.initials: P
authors.lastname: Delangle
mesh_terms: D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry* / Q000627:therapeutic use*; D003300:Copper / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D016503:Drug Delivery Systems; D015195:Drug Design; D006001:Glycoconjugates / Q000737:chemistry / Q000627:therapeutic use; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008668:Metallothionein / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D037263:Asialoglycoprotein Receptor; D002614:Chelating Agents; D006001:Glycoconjugates; D008024:Ligands; D003300:Copper; D008668:Metallothionein
keywords: Wilson's disease; copper(I); hepatic cells; sulfur ligands