Small molecule screening in context: lipid-catalyzed amyloid formation.
Small molecule screening in context: lipid-catalyzed amyloid formation.
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小分子筛选背景：脂质催化淀粉样蛋白形成。
DOI：
10.1002/pro.2518
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Miranker,AndrewD
中科院分区：
文献类型：
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作者：
Hebda,JamesA;Magzoub,Mazin;Miranker,AndrewD
胰岛淀粉样多肽（IAPP）是一种由胰腺β细胞与胰岛素共同分泌的37个残基的激素。IAPP的淀粉样纤维聚集与II型糖尿病患者中这些细胞的功能障碍和死亡相关。IAPP获得毒性功能的可能机制包括能量非依赖性细胞膜穿透和诱导膜去极化。这些过程与脂双层催化加速淀粉样蛋白形成的溶液生物物理观察相关。虽然淀粉样蛋白的形成和毒性之间的关系知之甚少，事实上，条件促进一个也有利于其他建议相关的膜活性结构状态。在这里，描述了一种新的高通量筛选方案，利用这种相关性来识别靶向膜活性物质的化合物。应用到一个小的库960已知的生物活性化合物，我们能够报告识别37种化合物，其中36个以前没有报道为积极对IAPP纤维形成。在次级细胞活力测定中测试的几种化合物也证明了细胞保护作用。一般观察到，在几种淀粉样蛋白疾病（如阿尔茨海默氏病和帕金森氏病）中肽诱导的毒性涉及膜结合的类淀粉样蛋白寡聚物种类。我们的数据表明，基于脂质催化组装的筛选方案将在淀粉样蛋白疾病的这一亚类中发现具有机械信息的小分子命中。
Islet Amyloid Polypeptide (IAPP) is a 37‐residue hormone cosecreted with insulin by the β‐cells of the pancreas. Amyloid fiber aggregation of IAPP has been correlated with the dysfunction and death of these cells in type II diabetics. The likely mechanisms by which IAPP gains toxic function include energy independent cell membrane penetration and induction of membrane depolarization. These processes have been correlated with solution biophysical observations of lipid bilayer catalyzed acceleration of amyloid formation. Although the relationship between amyloid formation and toxicity is poorly understood, the fact that conditions promoting one also favor the other suggests related membrane active structural states. Here, a novel high throughput screening protocol is described that capitalizes on this correlation to identify compounds that target membrane active species. Applied to a small library of 960 known bioactive compounds, we are able to report identification of 37 compounds of which 36 were not previously reported as active toward IAPP fiber formation. Several compounds tested in secondary cell viability assays also demonstrate cytoprotective effects. It is a general observation that peptide induced toxicity in several amyloid diseases (such as Alzhiemer's and Parkinson's) involves a membrane bound, preamyloid oligomeric species. Our data here suggest that a screening protocol based on lipid‐catalyzed assembly will find mechanistically informative small molecule hits in this subclass of amyloid diseases.