Chemical approaches to selectively target beta-rich amyloids

选择性靶向富含β淀粉样蛋白的化学方法

• 批准号: 10317223
• 负责人: Juan R Del Valle
• 金额: $ 49.54万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317223
• 关键词: Adopted; Alzheimer' s Disease; Alzheimer' s disease patient; Amination; Amyloid; Amyloid Proteins; Amyloidosis; Area; Binding; Biological; Biological Assay; Brain; Brain Diseases; Cells; Characteristics; Chemicals; Cryoelectron Microscopy; Cues; DNA; Data; Development; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Excision; Exhibits; Face; Filament; Fluorescence; Frontotemporal Dementia; Growth; Hydrogen Bonding; In Vitro; Inherited; Lead; Libraries; Ligands; Modeling; Modification; Molecular Conformation; Molecular Probes; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Pathogenicity; Pathologic; Patients; Peptide Hydrolases; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Pick Disease of the Brain; Play; Polymorph; Protein Conformation; Protein Isoforms; Proteins; Recombinants; Reporter; Research; Resistance; Resolution; Role; Scanning; Secondary Protein Structure; Series; Solid; Structure; Surface; System; Tertiary Protein Structure; Testing; Therapeutic; Translating; Vertebral column; alpha helix; amyloid formation; aqueous; base; beta pleated sheet; chemical synthesis; corticobasal degeneration; design; flexibility; inhibitor/antagonist; interest; mimicry; mutation screening; neurotoxic; novel; peptidomimetics; protein aminoacid sequence; protein folding; protein protein interaction; protein structure; solid state; tau Proteins; tau aggregation; tau mutation; transmission process; Adopted; Alzheimer' s Disease; Alzheimer' s disease patient; Amination; Amyloid; Amyloid Proteins; Amyloidosis; Area; Binding; Biological; Biological Assay; Brain; Brain Diseases; Cells; Characteristics; Chemicals; Cryoelectron Microscopy; Cues; DNA; Data; Development; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Excision; Exhibits; Face; Filament; Fluorescence; Frontotemporal Dementia; Growth; Hydrogen Bonding; In Vitro; Inherited; Lead; Libraries; Ligands; Modeling; Modification; Molecular Conformation; Molecular Probes; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Pathogenicity; Pathologic; Patients; Peptide Hydrolases; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Pick Disease of the Brain; Play; Polymorph; Protein Conformation; Protein Isoforms; Proteins; Recombinants; Reporter; Research; Resistance; Resolution; Role; Scanning; Secondary Protein Structure; Series; Solid; Structure; Surface; System; Tertiary Protein Structure; Testing; Therapeutic; Translating; Vertebral column; alpha helix; amyloid formation; aqueous; base; beta pleated sheet; chemical synthesis; corticobasal degeneration; design; flexibility; inhibitor/antagonist; interest; mimicry; mutation screening; neurotoxic; novel; peptidomimetics; protein aminoacid sequence; protein folding; protein protein interaction; protein structure; solid state; tau Proteins; tau aggregation; tau mutation; transmission process

PROJECT ABSTRACT Protein-protein interactions are governed by recognition events between peptide secondary structures (a- helices, b-sheets, loops), which in turn provide design cues for the development of selective chemical probes. However, removal of ordered peptide domains from the context of the surrounding tertiary structure compromises folding and conformational stability. Mimicry and disruption of b-strand/sheet interactions remains a considerable challenge. This is largely due to the inherent flexibility of short peptide sequences, the propensity for b-strands to aggregate, and the large surface areas and diverse modes of b-sheet packing. The early oligomerization of several amyloidogenic proteins involves conformational reorganization into parallel b-sheet structures, followed supramolecular assembly into toxic fibrils. Recent atomic-level structural data using patient-derived extracts has revealed that neurotoxic amyloids may be characterized by unique structural polymorphs, or ‘strains’, depending on the disease. Despite the need for amyloid- and strain-specific ligands, b-rich amyloid assemblies represent particularly challenging targets. We recently established peptide backbone N-amination as a subtle yet remarkably effective approach to b-strand/sheet stabilization. The conformational and non-aggregating characteristics of N-amino peptides (NAPs) render them uniquely suited for capping the growth of sheet fibrils while maintaining the facial packing and sidechain interdigitation important for amyloid recognition. Here, we will further develop soluble mimics of diverse b-sheet-like folds to disrupt amyloid aggregation in a sequence and strain-specific manner. As a proof-of-concept, we will target the assembly and cellular transmission of tau fibrils that characterize numerous sporadic and hereditary neurodegenerative disorders. Our overarching hypothesis is that the structural features of peptide N-amination will enable the development of ligands that selectively target b-rich amyloid folds. In Aim 1 we will expand the utility of NAP modification in pursuit of hyperstable b-strands and amyloid mimics based on parallel b-sheet macrocycles. A library of NAP-based tau mimics will be synthesized in Aim 2. These compounds will be evaluated for their ability to block aggregation and cellular transmission of recombinant tau fibrils as well those extracted from AD patients. In Aim 3, we will synthesize a series of aggregation-resistant NAP macrocycles that mimic the cross-b packing observed in pathogenic tau strains. These will be evaluated for their capacity to specifically inhibit cellular seeding by tau fibrils derived from AD and CBD brains. We anticipate that ligands emerging from this study will enable a robust examination of the the pathogenic strain model of tau transmission. More broadly, these studies will have a significant impact on the design of other selective disruptors of b-sheet and amyloid assemblies that are inherently difficult to target.

项目摘要 蛋白质 - 蛋白质相互作用受肽二级结构之间的识别事件的控制（A- 螺旋，b片，循环），这又为选择性化学问题的发展提供了设计线索。 但是，从周围的三级结构的上下文中删除有序的肽域妥协 折叠和构象稳定性。 b链/表相互作用的模仿和破坏仍然很大 挑战。这主要是由于短肽序列的继承灵活性，这是B链的承诺 汇总，较大的表面区域和大型B片包装模式。早期的寡聚化 几种淀粉样蛋白蛋白涉及会议重组为平行的B层结构，然后 超分子组装到有毒原纤维中。最近使用患者衍生提取物的原子级结构数据具有 揭示神经毒性淀粉样蛋白的特征是独特的结构多晶型或“菌株”，取决于 关于疾病。尽管需要淀粉样蛋白和应变特异性配体，但富含B的淀粉样蛋白组件代表 特别具有挑战性的目标。我们最近建立了肽主链N-杀剂作为微妙的 B链/薄板稳定的有效方法非常有效。构象和非聚集 N-氨基肽（NAP）的特征使它们独特地适合封闭片纤维的生长 同时保持面部包装和侧chain互插对于淀粉样蛋白识别很重要。在这里，我们会的 进一步开发潜水员b-折叠的固体模仿，以序列破坏淀粉样蛋白的聚集 应变特异性的方式。作为概念验证，我们将针对tau纤维的组装和细胞传递 这是许多零星和遗传神经退行性疾病的特征。我们的总体假设 是，胡椒n-施加的结构特征将使配体的发展有选择地靶向 B丰富的淀粉样蛋白褶皱。在AIM 1中，我们将扩大NAP修改的实用性，以追求昏迷的B链 基于平行的B片大环和淀粉样蛋白模拟物。基于小睡的tau模拟库将是 在AIM 2中合成。这些化合物的封闭能力和细胞的能力将被评估 重组Tau原纤维的传播以及从AD患者中提取的那些。在AIM 3中，我们将合成一个 一系列抗聚合的NAP大环，它们模仿了致病性tau中观察到的交叉B填料 菌株。这些将评估它们通过从 AD和CBD大脑。我们预计这项研究中出现的配体将使对 tau传播的致病应变模型。更广泛地，这些研究将对 B-sheet和淀粉样蛋白组件的其他选择性破坏者的设计本质上难以靶向。