Small molecule interference of bilayer catalyzed fiber formation

描述（申请人提供）：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个残基的肽激素。在II型糖尿病患者中，IAPP聚集为淀粉样蛋白纤维，其过程与？细胞功能障碍和随后的损失？- 细胞团。这是一个完全类似于其他蛋白质错误折叠疾病中明显的细胞毒性的过程，例如A？阿尔茨海默病的肽一般来说，淀粉样蛋白与细胞死亡的关联得到以下观察结果的支持：淀粉样蛋白前体的可溶性寡聚状态在添加到培养的细胞或注射到模型动物中时诱导疾病样毒性。观察到这些相同的状态与细胞膜相关，并且可以在体外透化脂质双层。这种相关性导致了这样的范例，即通过低聚状态（通过孔形成、地毯或洗涤剂样作用）的膜破坏是淀粉样疾病中细胞毒性的一般机制。我们最近的体外研究表明，IAPP可以结合脂双层的浓度远低于分泌颗粒中发现的。这种结合导致催化其转化为？- 片层丰富的淀粉样状态。有趣的是，IAPP最初稳定为？膜结合时的螺旋构象。这种状态，然后自我关联成膜结合，？- 螺旋低聚物。正是后者与淀粉样蛋白形成的催化和膜破坏两者相关。该提案的总体目标是筛选改变脂双层催化纤维形成的反应概况的小分子。以这种方式，将发现通过靶向一组离散的限定分子界面中的一个或多个来影响纤维形成的化合物。然后将评估这些分类介导膜不稳定和IAPP介导的细胞死亡的能力。在II型糖尿病患者中，制造胰岛素的细胞最终会失败。另一种称为胰岛淀粉样多肽（IAPP）的激素由相同的细胞产生，但可以形成对胰岛素分泌细胞有毒的结构。这项工作的目的是找到药物大小的分子，防止IAPP形成这些有毒结构。

DESCRIPTION (provided by applicant): Islet amyloid polypeptide (IAPP) is a 37 residue peptide hormone cosecreted with insulin by the beta-cells of the pancreas. In patients with type II diabetes, IAPP aggregates as amyloid fiber in a process that is associated with ?-cell dysfunction and the subsequent loss of ? -cell mass. This is a process wholly analogous to cytotoxicity evident in other protein misfolding diseases, e.g. A? peptide from Alzheimer's disease. In general, the association of amyloid with cell death is supported by the observation that soluble oligomeric states of amyloid precursors induce disease-like toxicity when added to cultured cells or injected into model animals. These same states are observed associated with cellular membranes and can permeablize lipid bilayers in vitro. This correlation has led to the paradigm that membrane disruption by oligomeric states, either through pore formation, carpet or detergent-like effects, is a general mechanism of cytotoxicity among amyloid diseases. Our recent investigations in vitro have revealed that IAPP can bind lipid bilayers at concentrations well below that found in the secretory granule. This binding results in catalysis of its conversion into the ? -sheet rich amyloid state. Intriguingly, IAPP is initially stabilized into an ?-helical conformation upon membrane binding. This state then self-associates into a membrane bound, ? -helical oligomer. It is the latter that is correlated both with catalysis of amyloid formation, and with membrane disruption. The overall aim of this proposal is to screen for small molecules that alter the reaction profile of lipid bilayer catalyzed fiber formation. In this way, compounds will be found that affect fiber formation by targeting one of more of a discrete set of defined molecular interfaces. These categorizations will be then assessed with respect to their capacity to mediate membrane destabilization and IAPP mediated cell death. In patients with type II diabetes, the cells which make insulin eventually fail. Another hormone called islet amyloid polypeptide (IAPP) is made by the same cells, but can form structures which are toxic to the insulin secreting cells. The aim of this work is to find drug-sized molecules which prevent IAPP from forming these toxic structures.