Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.
Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.
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DOI：
10.7554/elife.00857
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发表时间：
2013-07-16
期刊：
影响因子：
7.7
通讯作者：
Eisenberg DS
中科院分区：
文献类型：
--
作者：
Jiang L;Liu C;Leibly D;Landau M;Zhao M;Hughes MP;Eisenberg DS
淀粉样蛋白聚集体与数十种毁灭性疾病有关，包括阿尔茨海默氏症、帕金森症、ALS和2型糖尿病。虽然基于结构的化合物发现在对抗许多感染性和代谢性疾病方面是有效的，但对淀粉样蛋白结构的无知阻碍了对淀粉样蛋白疾病的类似研究。在这里，我们展示了对阿尔茨海默病淀粉样蛋白（Aβ）粘附的一个立体拉链片段的原子结构的了解，当与计算方法相结合时，识别出8种不同但主要是扁平的化合物和3种化合物衍生物，这些化合物可将Aβ对哺乳动物细胞的毒性降低高达90%。虽然这些化合物与Aβ纤维结合，但它们不减少Aβ纤维的形成。纤维结合化合物及其衍生物的构效关系研究表明，化合物结合可能通过将Aβ的平衡从低聚物转移到纤维中来增加纤维的稳定性并降低纤维的毒性。DOI: http://dx.doi.org/10.7554/eLife.00857.001阿尔茨海默病是最常见的痴呆症，据估计在美国大约有500万人受到影响，随着人口老龄化，其发病率正在稳步上升。阿尔茨海默病的病理特征是大脑中存在两种蛋白质的聚集体：一种叫做tau的蛋白质的缠结；纤维和一种叫做淀粉样蛋白的肽的较小单位（低聚物）。人们已经做了许多尝试来筛选天然和合成化合物的文库，以确定可能阻止淀粉样蛋白聚集和毒性的物质。这些研究表明，绿茶和香料姜黄中的多酚可以抑制淀粉样蛋白原纤维的形成。此外，许多染料减少了淀粉样蛋白对细胞的毒性作用，尽管显著的副作用阻止了它们被用作药物。基于结构的药物设计，利用目标蛋白的结构来帮助识别与之相互作用的化合物，已被用于产生治疗许多疾病的药物。在这里，Jiang等人报道了该技术在寻找抑制β淀粉样蛋白细胞毒性的化合物中的首次应用。Jiang等人利用已知的蛋白质与染料复合物的原子结构，对18000种化合物进行了计算筛选，以寻找那些可能有效结合的化合物。研究人员随后测试了显示出最强预测结合的化合物对淀粉样蛋白聚集的干扰能力，以及保护培养细胞免受其毒性影响的能力。降低毒性的化合物并没有减少蛋白质聚集体的丰度，但它们似乎增加了原纤维的稳定性。这与其他证据一致，这些证据表明，从原纤维中分离出来的β淀粉样蛋白的小而可溶形式（低聚物）可能是阿尔茨海默病的有毒物质，而不是原纤维本身。除了发现在阿尔茨海默病中具有治疗潜力的化合物外，这项工作还提出了一种识别与淀粉样蛋白原纤维结合的蛋白质的新方法。鉴于淀粉样蛋白积累是许多其他疾病的特征，包括帕金森氏病、亨廷顿氏病和2型糖尿病，这种方法可能有广泛的治疗应用。DOI: http://dx.doi.org/10.7554/eLife.00857.002
Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer’s, Parkinson’s, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer’s disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers. DOI: http://dx.doi.org/10.7554/eLife.00857.001 Alzheimer’s disease is the most common form of dementia, estimated to affect roughly five million people in the United States, and its incidence is steadily increasing as the population ages. A pathological hallmark of Alzheimer’s disease is the presence in the brain of aggregates of two proteins: tangles of a protein called tau; and fibers and smaller units (oligomers) of a peptide called amyloid beta. Many attempts have been made to screen libraries of natural and synthetic compounds to identify substances that might prevent the aggregation and toxicity of amyloid. Such studies revealed that polyphenols found in green tea and in the spice turmeric can inhibit the formation of amyloid fibrils. Moreover, a number of dyes reduce the toxic effects of amyloid on cells, although significant side effects prevent these from being used as drugs. Structure-based drug design, in which the structure of a target protein is used to help identify compounds that will interact with it, has been used to generate therapeutic agents for a number of diseases. Here, Jiang et al. report the first application of this technique in the hunt for compounds that inhibit the cytotoxicity of amyloid beta. Using the known atomic structure of the protein in complex with a dye, Jiang et al. performed a computational screen of 18,000 compounds in search of those that are likely to bind effectively. The compounds that showed the strongest predicted binding were then tested for their ability to interfere with the aggregation of amyloid beta and to protect cells grown in culture from its toxic effects. Compounds that reduced toxicity did not reduce the abundance of protein aggregates, but they appear to increase the stability of fibrils. This is consistent with other evidence suggesting that small, soluble forms (oligomers) of amyloid beta that break free from the fibrils may be the toxic agent in Alzheimer’s disease, rather than the fibrils themselves. In addition to uncovering compounds with therapeutic potential in Alzheimer’s disease, this work presents a new approach for identifying proteins that bind to amyloid fibrils. Given that amyloid accumulation is a feature of many other diseases, including Parkinson’s disease, Huntington’s disease and type 2 diabetes, the approach could have broad therapeutic applications. DOI: http://dx.doi.org/10.7554/eLife.00857.002