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37个残基的多肽激素，由胰腺的β细胞与胰岛素共分泌。在II型糖尿病患者中，IAPP以淀粉样纤维的形式聚集，这一过程与？细胞功能障碍和随后的？细胞质量丧失有关。这一过程完全类似于在其他蛋白质错折叠疾病中明显存在的细胞毒性，例如A？来自阿尔茨海默氏症的多肽。总体而言，淀粉样前体的可溶性低聚状态在加入培养细胞或注射到模型动物中时会引起类疾病毒性，这一观察结果支持了淀粉样蛋白与细胞死亡的联系。这些相同的状态与细胞膜相关，并能在体外渗透脂双层。这种相关性导致了一种范式，即低聚状态通过孔道形成、地毯或洗涤剂样效应破坏细胞膜是淀粉样疾病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，其浓度远低于分泌颗粒中的浓度。这种结合导致其转化为富含β-片状淀粉样蛋白的催化作用。有趣的是，IAPP最初在膜结合时稳定为？螺旋构象。然后，这种状态自结合成膜结合的螺旋低聚物。后者既与淀粉样蛋白形成的催化有关，也与膜的破坏有关。这项建议的总体目标是筛选能够改变脂双层催化纤维形成的反应轮廓的小分子。通过这种方式，将发现通过锁定一组离散的已定义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在介导膜失稳和IAPP介导的细胞死亡方面的能力。在II型糖尿病患者中，制造胰岛素的细胞最终会失效。另一种名为胰岛淀粉样多肽(IAPP)的激素是由相同的细胞制造的，但可以形成对胰岛素分泌细胞有毒的结构。这项工作的目的是寻找药物大小的分子，以防止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.