Small molecule interference of bilayer catalyzed fiber formation

双层催化纤维形成的小分子干扰

• 批准号: 7530251
• 负责人: ANDREW D. MIRANKER
• 金额: $ 22.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530251
• 关键词: Abbreviations; Affect; Alzheimer' s Disease; Amyloid; Amyloid fibers; Amyloidosis; Animal Model; Animals; Beta Cell; Binding; Biological Assay; Carpet; Catalysis; Categories; Cell Death; Cell membrane; Cells; Cellular Membrane; Chemicals; Choline; Class; Complex; Cultured Cells; Detergents; Dimethyl Sulfoxide; Disease; Disruption; Electron Microscopy; Energy Transfer; Extravasation; Fiber; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Glycerol; Helix (Snails); Hormones; Human; In Vitro; Insulin; Investigation; Lipid Bilayers; Lipid Binding; Liposomes; Magnetism; Mediating; Membrane; Membrane Proteins; Molecular; Molecular Conformation; Natural Killer Cells; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Numbers; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipids; Plasma; Process; Proteins; Range; Rattus; Reaction; Screening procedure; Secretory Vesicles; Site; Spectrum Analysis; Structure; Structure of beta Cell of islet; Thioflavin T; Toxic effect; Work; amyloid formation; base; catalyst; cytotoxicity; ear helix; fibrillogenesis; insight; islet amyloid polypeptide; peptide A; peptide hormone; prevent; protein aggregate; protein misfolding; segregation; self assembly; size; small molecule; success

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.

描述（由申请人提供）：胰岛淀粉样蛋白多肽（IAPP）是胰腺β细胞与胰岛素共同分泌的一种37残基肽激素。在2型糖尿病患者中，IAPP以淀粉样蛋白纤维的形式聚集，其过程与？-细胞功能障碍和随后的？电池质量。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了观察的支持，即淀粉样蛋白前体的可溶性低聚状态在添加到培养细胞或注射到模型动物中时会诱导类似疾病的毒性。这些相同的状态被观察到与细胞膜相关，并且可以在体外穿透脂质双分子层。这种相关性导致了一种范式，即低聚物状态通过孔隙形成、地毯或洗涤剂样作用破坏膜，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可以在浓度远低于分泌颗粒的情况下结合脂质双分子层。这种结合导致其催化转化为？-片状丰富的淀粉样蛋白状态。有趣的是，IAPP最初稳定为？-膜结合时的螺旋构象。然后这种状态自我结合成膜结合，？螺旋低聚物。后者与淀粉样蛋白形成的催化作用和膜破坏有关。本提案的总体目标是筛选改变脂质双分子层催化纤维形成反应的小分子。通过这种方式，将发现化合物通过靶向一个或多个离散的定义分子界面来影响纤维的形成。这些分类随后将评估其介导膜不稳定和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衰竭。另一种叫做胰岛淀粉样多肽（IAPP）的激素也是由同样的细胞产生的，但它形成的结构对胰岛素分泌细胞是有毒的。这项工作的目的是找到药物大小的分子，阻止IAPP形成这些有毒结构。