Folded small molecule manipulation of islet amyloid polypeptide.
Folded small molecule manipulation of islet amyloid polypeptide.
复制标题
胰岛淀粉样多肽的折叠小分子操作。
DOI：
10.1016/j.chembiol.2014.05.007
复制
发表时间：
2014
影响因子：
--
通讯作者：
Miranker,AndrewD
中科院分区：
文献类型：
--
作者：
Kumar,Sunil;Brown,MarkA;Nath,Abhinav;Miranker,AndrewD
胰岛淀粉样多肽（Islet amyloid polypeptide，IAPP）是胰岛β细胞分泌的一种与胰岛素共分泌的激素。在与脂质双层接触时，它被稳定成结构状态的异质系综。这些过程与功能的获得相关，包括富含β片层的淀粉样蛋白形成的催化、细胞膜渗透、膜完整性的丧失和细胞毒性。这些导致β细胞功能障碍，β细胞是糖尿病病理学和治疗的核心组成部分。为了深入了解这些现象，设计了一系列相关的取代寡喹啉。这些抑制剂是独特的，因为它们具有影响溶液和磷脂双层催化的IAPP自组装的能力。重要的是，我们表明，这种活性与oligoquinoline不可逆地通过非共价折叠的能力有关。这表明，紧凑的折叠体支架，如低聚喹啉，是一个重要的范例构象操纵无序的蛋白质状态。
Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin by pancreatic β cells. Upon contact with lipid bilayers, it is stabilized into a heterogeneous ensemble of structural states. These processes are associated with gains of function, including catalysis of β sheet-rich amyloid formation, cell membrane penetration, loss of membrane integrity, and cytotoxicity. These contribute to the dysfunction of β cells, a central component in the pathology and treatment of diabetes. To gain mechanistic insight into these phenomena, a related series of substituted oligoquinolines were designed. These inhibitors are unique in that they have the capacity to affect both solution- and phospholipid bilayer-catalyzed IAPP self-assembly. Importantly, we show that this activity is associated with the oligoquinoline's capacity to irreversibly adopt a noncovalent fold. This suggests that compact foldamer scaffolds, such as oligoquinoline, are an important paradigm for conformational manipulation of disordered protein state.