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: 10461957
• 负责人: Juan R Del Valle
• 金额: $ 48.12万
• 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/10461957
• 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; 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-蛋白质相互作用由肽二级结构之间的识别事件控制（a- 螺旋、b-折叠、环），这反过来又为选择性化学探针的开发提供了设计线索。 然而，从周围三级结构的背景中去除有序肽结构域会损害 折叠和构象稳定性。 b 链/片层相互作用的模仿和破坏仍然是相当大的 挑战。这主要是由于短肽序列固有的灵活性、b 链的倾向 聚合，以及大表面积和多样化的b片包装方式。早期寡聚化 几种淀粉样蛋白涉及构象重组为平行的 b-片结构，随后 超分子组装成有毒原纤维。最近使用患者提取物获得的原子级结构数据 揭示神经毒性淀粉样蛋白可能具有独特的结构多晶型物或“菌株”的特征，具体取决于 关于疾病。尽管需要淀粉样蛋白和菌株特异性配体，但富含 b 的淀粉样蛋白组装体代表 特别具有挑战性的目标。我们最近建立了肽骨架 N-氨基化作为一种​​微妙的但 非常有效的 b 链/片层稳定方法。构象和非聚集 N-氨基肽 (NAP) 的特性使其特别适合限制片状原纤维的生长 同时保持对淀粉样蛋白识别很重要的面部堆积和侧链交叉。在这里，我们将 进一步开发多种b-片状折叠的可溶性模拟物，以破坏序列中的淀粉样蛋白聚集，并 菌株特异性方式。作为概念验证，我们将针对 tau 原纤维的组装和细胞传输 这是许多散发性和遗传性神经退行性疾病的特征。我们的总体假设 肽 N-氨基化的结构特征将有助于开发选择性靶向的配体 富含b的淀粉样蛋白折叠。在目标 1 中，我们将扩展 NAP 修饰的效用，以追求超稳定的 b 链 和基于平行b-片大环的淀粉样蛋白模拟物。基于 NAP 的 tau 模拟物库将 在目标 2 中合成。将评估这些化合物阻止聚集和细胞的能力 重组 tau 原纤维以及从 AD 患者中提取的原纤维的传播。在目标 3 中，我们将合成一个 一系列抗聚集的 NAP 大环化合物，模拟致病性 tau 蛋白中观察到的交叉 b 堆积 菌株。将评估它们特异性抑制来自以下来源的 tau 原纤维的细胞播种的能力： AD 和 CBD 大脑。我们预计本研究中出现的配体将能够对 tau 传播的致病菌株模型。更广泛地说，这些研究将对 b-折叠和淀粉样蛋白组装体的其他选择性破坏剂的设计本质上难以靶向。