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.

Update on the clinical management of Wilson's disease

“…This strategy for chelating intracellular copper is expected to avoid systemic toxicity caused by excessive release of copper from the liver and thus, maintaining free copper plasma in the safe range. One example of this concept is a novel chelator that is a tripodal cysteine-based ligand inspired by metallothioneins 85,86. Its high affinity to the liver has been achieved with specific recognition elements of the asialoglycoprotein receptor that is specific for targeting hepatocytes.…”

d-Penicillamine Tripodal Derivatives as Efficient Copper(I) Chelators

“…However, some side effects related to this therapy have been reported. 14 More precisely, it has been shown that D-Pen can contribute to increase the neurologic deterioration expressed by some Wilson's disease patients, which may be due to a lack of specificity of the drug.…”

Total Biosynthesis and Diverse Applications of the Nonribosomal Peptide-Polyketide Siderophore Yersiniabactin

“…In the biomedical community, Ybt was recently recognized for a parallel ability to bind and sequester copper (23,24). The potential to selectively bind copper also holds promise in treating Wilson's disease, in which an excess of this metal accumulates in tissue (25)(26)(27). These and other situations will benefit from the recombinant capabilities that accompany the production of Ybt, and likely future siderophore products, when genetically tractable heterologous hosts such as E. coli are used.…”