Chelation therapy in Wilson's disease: from d-penicillamine to the design of selective bioinspired intracellular Cu(i) chelators

Abstract

Wilson's disease is an orphan disease due to copper homeostasis dysfunction. Mutations of the ATP7B gene induces an impaired functioning of a Cu-ATPase, impaired Cu detoxification in the liver and copper overload in the body. Indeed, even though copper is an essential element, which is used as cofactor by many enzymes playing vital roles, it becomes toxic when in excess as it promotes cytotoxic reactions leading to oxidative stress. In this perspective, human copper homeostasis is first described in order to explain the mechanisms promoting copper overload in Wilson's disease. We will see that the liver is the main organ for copper distribution and detoxification in the body. Nowadays this disease is treated life-long by systemic chelation therapy, which is not satisfactory in many cases. Therefore the design of more selective and efficient drugs is of great interest. A strategy to design more specific chelators to treat localized copper accumulation in the liver will then be presented. In particular we will show how bioinorganic chemistry may help in the design of such novel chelators by taking inspiration from the biological copper cell transporters.

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

“…aS (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) Ascorbate stock solution (0.1 m)f or NMR analysis and UV-ROS analysis was freshly prepared daily by weighing powder (19.8 mg) and dissolving it in pure water (1 mL). The concentration of ascorbic acid was also estimated during ROS analysis with use of the molar extinction coefficient of 14 500 m À1 cm À1 at 265 nm (0.1 mm solution correspond to an absorbance of 1.45) All other reagents were purchased from Sigma-Aldrich.…”

“…An important mechanism for toxicity in the copper overloadi st he capability of free or loosely bound cooper to catalyset he productionofr eactive oxygen species (ROS). [1,2] Mismetabolism of copperh as been reported in several neurodegenerative diseases, such as Alzheimer's disease (AD), [3] Parkinson'sd isease (PD), [4][5][6] prion disease, [7,8] and amyotrophic lateral sclerosis. [9,10] Often Cu is found to be bound to ad isease-specific amyloidogenic peptide or protein.…”

Nephrotic syndrome after treatment with D-penicillamine in a patient with Wilson’s disease

“…More than 500 mutations are known (1). Copper is an essential trace element, which is used as a cofactor by many enzymes playing vital roles but in WD it is accumulated to the point of toxicity (2). Clinical manifestation of WD is due to copper overload of copper in liver, brain, cornea, kidneys, and in other organs and tissues.…”

“…Renal symptoms occur only in 1% of patients (4) usually as renal insufficiency with fulminant hepatic failure and hemolysis. WD is fatal if untreated (1,2,5). D-Penicillamine (D-PA) is a classic drug for treatment of WD and has been used frequently as first line therapy (6).…”

Bioavailable Trace Metals in Neurological Diseases

“…Further treatments should focus on more sitespecific copper chelators that can act in the hepatocytes to excrete the coppercomplex into the bile. Gene therapy also seems an attractive alternative with effective treatment on WD animal models [21,22].…”