Insight into pathological self assembly using alpha-helical mimetics

使用α螺旋模拟物洞察病理自组装

• 批准号: 8243517
• 负责人: ANDREW D. MIRANKER
• 金额: $ 31.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243517
• 关键词: Adopted; Alzheimer' s Disease; Amides; Amyloid; Amyloid deposition; Amyloidosis; Attenuated; Behavior; Beta Cell; Binding; Binding Proteins; Binding Sites; Biological; Biological Assay; Biological Availability; Biophysics; Cell Death; Cell Survival; Cells; Cellular biology; Chemicals; Collaborations; Complex; Computing Methodologies; Coupled; Cytoplasm; Deposition; Development; Diabetes Mellitus; Disease; Docking; Eukaryotic Cell; Extravasation; Fiber; Goals; Golgi Apparatus; Grouping; In Vitro; Insulin; Investigation; Islets of Langerhans; Laboratories; Lead; Libraries; Life; Lipid Bilayers; Location; Mediating; Membrane; Membrane Proteins; Methods; Molecular; Mutagenesis; Nature; Non-Insulin-Dependent Diabetes Mellitus; Organic Synthesis; Pathology; Pathway interactions; Phase; Postdoctoral Fellow; Process; Protein Precursors; Proteins; Reaction; Resolution; Secretory Vesicles; Senile Plaques; Shapes; Site; Solid; Solutions; Structure; Students; Surface; Synthesis Chemistry; System; Techniques; Testing; Toxic effect; Work; base; cell type; computational chemistry; cytotoxic; cytotoxicity; design; diabetic; enzyme activity; improved; in vivo; insight; insulin secretion; islet; islet amyloid polypeptide; lipid metabolism; mimetics; novel; peptide hormone; protein structure; public health relevance; receptor; self assembly; small molecule; structural biology; tool

DESCRIPTION (provided by applicant): The primary goal of this proposal is the design of small molecule compounds which target newly identified protein structures with direct relevance to insulin secreting 2-cell viability in type II diabetes. Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone, which is co-secreted with insulin by the 2-cells of the endocrine pancreas. IAPP belongs to a class of aggregation prone proteins, which includes A2 from Alzheimer's, in which a wild-type protein precursor irreversibly forms/folds into 2-sheet rich fibrillar amyloid plaques. The origin of 2-cell death in type II diabetes is poorly understood. Like most amyloid diseases, it is the presence, rather than the extent, of amyloid deposition that is correlated with pathology. Instead, it is the intermediates of the assembly reaction that have been implicated in cell death. Importantly, this cytotoxicity is mediated by the formation of membrane bound protein structures. In the case of IAPP, this is highly intriguing since, despite the 2-sheet nature of mature amyloid, membrane bound states are 1-helical. The overall hypothesis pursued by this proposal is that small-molecule, structure based targeting of pre-amyloidogenic states will enable elucidation of the mechanism of IAPP induced cytotoxicity. These efforts will provide novel descriptions of IAPP oligomerization at a molecular level, and provide a rational design path for the creation of lead compounds that ameliorate 2-cell death. Our concurrently pursued aims include synergistic efforts in synthetic chemistry, cell and structural biology. Importantly, we will target the 1-helical intermediates of IAPP by synthesizing small molecules designed to mimic the surface presentation of one edge of an 1-helix. Cellular methods will be developed to assess toxicity and localization of IAPP. Diffraction, NMR and computational methods will be employed to elucidate the alternative oligomeric states at atomic resolution and to provide structure based guidance for small molecule synthesis. PUBLIC HEALTH RELEVANCE: Changes to the shape of a protein surface can result in its inadvertent assembly into toxic structures. This process occurs in numerous diseases including type II diabetes and Alzheimer's. A novel synthetic chemistry approach is proposed that allows for the mimicking of protein surface using small molecules. This will enable the testing of hypotheses about the molecular basis of toxicity in the insulin secreting cells of type II diabetics.

描述(由申请人提供)：这项建议的主要目标是设计小分子化合物，其目标是新发现的与II型糖尿病患者胰岛素分泌2细胞活性直接相关的蛋白质结构。胰岛淀粉样多肽(IAPP)是一种37个残基的多肽激素，由胰腺内分泌的2-细胞与胰岛素共同分泌。IAPP属于一类易于聚集的蛋白质，其中包括阿尔茨海默病的A2，其中野生型蛋白前体不可逆转地形成/折叠成富含2层纤维的淀粉样斑块。II型糖尿病中2-细胞死亡的原因还知之甚少。像大多数淀粉样病一样，与病理相关的是淀粉样蛋白沉积的存在，而不是沉积的程度。相反，与细胞死亡有关的是组装反应的中间产物。重要的是，这种细胞毒性是由膜结合蛋白结构的形成所介导的。在IAPP的情况下，这是非常有趣的，因为尽管成熟的淀粉样蛋白具有2页的性质，但膜结合的状态是1螺旋的。这一建议所追求的总体假设是，以小分子、基于结构的靶向前淀粉样变状态将有助于阐明IAPP诱导的细胞毒性的机制。这些工作将在分子水平上为IAPP齐聚提供新的描述，并为创造改善2-细胞死亡的先导化合物提供合理的设计途径。我们同时追求的目标包括在合成化学、细胞和结构生物学方面的协同努力。重要的是，我们将通过合成小分子来瞄准IAPP的1-螺旋中间体，这些小分子旨在模拟1-螺旋的一个边缘的表面呈现。将开发细胞方法来评估IAPP的毒性和定位。我们将利用衍射、核磁共振和计算方法来阐明原子分辨率下的替代低聚态，并为小分子的合成提供基于结构的指导。 与公共健康相关：蛋白质表面形状的变化可能会导致其无意中组装成有毒结构。这一过程发生在许多疾病中，包括II型糖尿病和阿尔茨海默氏症。有人提出了一种新的合成化学方法，允许使用小分子模拟蛋白质表面。这将使关于II型糖尿病患者胰岛素分泌细胞毒性的分子基础的假设得到验证。