An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.
An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.
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DOI：
10.1126/sciadv.1501244
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发表时间：
2016-02
期刊：
影响因子：
13.6
通讯作者：
Vendruscolo M
中科院分区：
文献类型：
--
作者：
Habchi J;Arosio P;Perni M;Costa AR;Yagi-Utsumi M;Joshi P;Chia S;Cohen SI;Müller MB;Linse S;Nollen EA;Dobson CM;Knowles TP;Vendruscolo M
一种批准的抗癌药物选择性地针对导致阿尔茨海默病的分子级联的第一步。β-淀粉样蛋白(A-β)多肽转化为致病聚集体与阿尔茨海默病的发生和发展有关。尽管这一观察结果促使人们广泛寻找治疗药物来调节Aβ的浓度或抑制其聚集，但到目前为止，所有以这些目标为目标的临床试验都失败了，至少部分原因是缺乏对聚集过程及其抑制的分子机制的了解。为了解决这个问题，我们描述了一种理性药物发现的化学动力学方法，其中定量地分析了小分子对Aβ42自组装中特定微观步骤速率的影响，Aβ42是A DNA最容易聚集的变体。通过应用这种方法，我们报道了美国食品和药物管理局批准的抗癌药物贝沙罗汀选择性地靶向Aβ42聚集的主要成核步骤，延迟神经母细胞瘤细胞中有毒物种的形成，并在Aβ42介导的线虫毒性模型中完全抑制Aβ42的沉积及其后果。这些结果表明，通过贝沙罗汀等化合物防止Aβ42的初级成核可能会潜在地降低阿尔茨海默病的发病风险，更广泛地说，我们的策略为合理确定一系列针对神经退行性疾病的候选药物提供了一个总体框架。
An approved anticancer drug selectively targets the first step in the molecular cascade resulting in Alzheimer’s disease. The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer’s disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer’s disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.