Lanza Valeria, Milardi Danilo, Di Natale Giuseppe, Pappalardo Giuseppe
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Catania, Italy.
Curr Med Chem. 2018 Feb 12;25(4):525-539. doi: 10.2174/0929867324666170518094404.
There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration.
Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs.
Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease.
In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials.
寻找治疗神经退行性疾病的新药变得愈发紧迫。大量综述详尽描述了神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）的分子或临床方面。相反，关于用于其他疾病的已知药物如何也能作为神经退行性疾病治疗药物发挥作用的报道较少。本综述聚焦于一些铜（II）螯合分子作为神经退行性疾病潜在候选药物的当前用途。
从金属动态平衡失调与管理不善和AD发病之间存在的已知有害关系出发，我们调查了文献中报道的关于神经退行性疾病领域金属螯合药物重新定位的实验工作。综述论文从常见文献中检索，其选择限于描述与神经保护相关生物分子方面的论文。特别是，我们强调了所选药物的铜（II）配位能力。
已知铜与锌和铁一起在调节神经元功能中起关键作用。铜动态平衡的变化对几种神经退行性疾病至关重要。本综述纳入的研究可能概述了当前旨在将铜（II）螯合药物重新用于治疗神经退行性疾病的策略。从氯碘羟喹重新定位的典型案例出发，我们讨论了其他金属螯合药物（如PBT - 2、二甲双胍和环二肽）重新定位在神经退行性疾病治疗中可能带来的挑战和机遇。
为了提高药物重新定位的成功率，仍需要对分子机制和治疗效果进行全面研究。本综述认为药物重新定位比药物发现具有显著优势，因为重新定位的药物已经通过了安全性和毒性测试。如果有关于其作用机制的足够详细信息以鼓励进一步研究和临床试验，神经退行性疾病中有望的候选药物可能由铜螯合类药物代表。
