Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators
Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators
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DOI：
10.1039/c2dt12188c
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Mintz, Elisabeth
中科院分区：
文献类型：
--
作者：
Delangle, Pascale;Mintz, Elisabeth
肝豆状核变性是一种由于铜稳态功能障碍引起的罕见病。ATP 7 B基因的突变会导致Cu-ATP酶功能受损，肝脏中的铜解毒功能受损，以及体内的铜过载。事实上，尽管铜是一种必需元素，被许多发挥重要作用的酶用作辅因子，但当过量时，它会变得有毒，因为它会促进导致氧化应激的细胞毒性反应。从这个角度来看，人类铜稳态首先描述，以解释机制，促进铜超载威尔逊病。我们将看到肝脏是铜在体内分布和解毒的主要器官。目前，这种疾病是终身治疗的全身螯合治疗，这是不令人满意的，在许多情况下。因此，设计更有选择性和更有效的药物是非常有意义的。一个策略，设计更具体的螯合剂，以治疗局部铜蓄积在肝脏中，然后将提交。特别是，我们将展示如何生物无机化学可能有助于设计这种新的螯合剂从生物铜细胞转运的灵感。
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 lifelong 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.