Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Islets. 2009 Nov-Dec;1(3):210-5. doi: 10.4161/isl.1.3.9609.
Amyloid fibril formation is a common event in more than twenty human diseases and in some normal physiological processes. The mechanism of this ordered aggregation process and the molecular forces driving it are therefore of great importance. One of the strategies used in this field is targeting the fibrillization process by different factors, like, short peptides, organic molecules, etc. Here, we targeted insulin fibril formation by a range of small aromatic molecules, with different numbers of aromatic rings and various substituent groups. Using Thioflavin T fluorescence assay and transmission electron microscopy, we found that all dicyclic and tricyclic compounds in our screen were efficient inhibitors of insulin fibril formation. A common notion regarding amyloid inhibitors is that two functional groups are essentials for interfering with the amyloid formation process; a recognition motif and a bulky group for inducing a steric interference. However, here, we showed that some monocyclic compounds as small as toluene were also found to inhibit fibrillization. In addition, we found that substituent of benzene ring have a great influence on the inhibitory potency. Specifically, cyano, methyl and nitro groups increased the inhibitory potency. The results introduced here may contribute to future rational design of amyloid inhibitors.
淀粉样纤维形成是 20 多种人类疾病和某些正常生理过程中的常见事件。因此，这种有序聚集过程的机制和驱动它的分子力非常重要。该领域采用的策略之一是通过各种因素靶向纤维形成过程，如短肽、有机分子等。在这里，我们通过一系列具有不同数量芳香环和各种取代基的小分子靶向胰岛素纤维形成。使用硫黄素 T 荧光测定法和透射电子显微镜，我们发现筛选出的所有二环和三环化合物都是胰岛素纤维形成的有效抑制剂。关于淀粉样蛋白抑制剂的一个常见观点是，两个功能基团对于干扰淀粉样蛋白形成过程是必不可少的；一个识别基序和一个大体积基团用于诱导空间干扰。然而，在这里，我们发现一些小到甲苯的单环化合物也被发现能够抑制纤维形成。此外，我们发现苯环的取代基对抑制效力有很大影响。具体来说，氰基、甲基和硝基增加了抑制效力。这里介绍的结果可能有助于未来对淀粉样蛋白抑制剂进行合理设计。
