Structure-Based Small Molecule Modulation of a Pre-Amyloid State: Pharmacological Enhancement of IAPP Membrane-Binding and Toxicity.
Structure-Based Small Molecule Modulation of a Pre-Amyloid State: Pharmacological Enhancement of IAPP Membrane-Binding and Toxicity.
复制标题
基于结构的前淀粉样蛋白状态的小分子调节：IAPP 膜结合和毒性的药理学增强。
DOI：
10.1021/acs.biochem.5b00052
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发表时间：
2015
期刊：
影响因子：
2.9
通讯作者：
Miranker,AndrewD
中科院分区：
文献类型：
--
作者：
Nath,Abhinav;Schlamadinger,DianaE;Rhoades,Elizabeth;Miranker,AndrewD
胰岛淀粉样多肽（IAPP）是一种肽类激素，其病理性自组装是II型糖尿病进展的标志。IAPP-膜相互作用催化其高阶自组装，也是其对细胞毒性作用的基础。虽然人们对开发能够改变寡聚的膜结合IAPP的结构和行为的小分子试剂有很大的兴趣，但这种体系的动态和异质性使其与传统方法格格不入。在这里，我们建立在最近的见解膜结合状态的性质，并制定了一个计算和实验相结合的策略来解决这个问题。广义的结构方法有效地确定了不同的化合物从大型商业图书馆与以前未被识别的活动对获得的功能行为的IAPP。使用适当的计算预筛选减少了实验负担的数量级相对于无偏高通量筛选。我们发现，合理地靶向实验衍生的膜结合二聚体模型，确定了几种化合物，表现出显着的能力，以提高IAPP-膜结合和一种化合物，提高IAPP介导的细胞毒性。两者合计，这些研究结果意味着，膜bindingper seis不足以产生细胞毒性，相反，增强采样罕见的国家内的膜结合合奏可能会加强IAPP的毒性作用。
Islet amyloid polypeptide (IAPP) is a peptide hormone whose pathological self-assembly is a hallmark of the progression of type II diabetes. IAPP–membrane interactions catalyze its higher-order self-assembly and also underlie its toxic effects toward cells. While there is great interest in developing small molecule reagents capable of altering the structure and behavior of oligomeric, membrane-bound IAPP, the dynamic and heterogeneous nature of this ensemble makes it recalcitrant to traditional approaches. Here, we build on recent insights into the nature of membrane-bound states and develop a combined computational and experimental strategy to address this problem. The generalized structural approach efficiently identified diverse compounds from large commercial libraries with previously unrecognized activities toward the gain-of-function behaviors of IAPP. The use of appropriate computational prescreening reduced the experimental burden by orders of magnitude relative to unbiased high-throughput screening. We found that rationally targeting experimentally derived models of membrane-bound dimers identified several compounds that demonstrate the remarkable ability to enhance IAPP–membrane binding and one compound that enhances IAPP-mediated cytotoxicity. Taken together, these findings imply that membrane bindingper seis insufficient to generate cytotoxicity; instead, enhanced sampling of rare states within the membrane-bound ensemble may potentiate IAPP’s toxic effects.