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

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（a-10）之间的识别事件控制。 螺旋、B-片层、环），其又为选择性化学探针的开发提供设计线索。 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/折叠相互作用的模拟和破坏仍然是一个相当大的问题。 挑战.这在很大程度上是由于短肽序列固有的灵活性， 以及大的表面积和多种形式的B-片填料。的早期寡聚化 几种淀粉样蛋白涉及构象重组成平行的b-折叠结构， 超分子组装成有毒纤维。最近使用患者提取物的原子级结构数据 揭示了神经毒性淀粉样蛋白的特征可能是独特的结构多晶型物，或'应变'，这取决于 关于这种疾病。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了 特别是具有挑战性的目标。我们最近建立了肽骨架N-氨基化作为一种微妙的， 这是一种非常有效的方法来稳定B股/片材。构象和非聚集性 N-氨基肽（NAPs）的特性使它们独特地适合于覆盖片状原纤维的生长 同时保持对淀粉样蛋白识别重要的面堆积和侧链交错。在这里，我们将 进一步开发不同b折叠样折叠的可溶性模拟物以破坏序列中的淀粉样蛋白聚集， 具体的方式。作为概念验证，我们将针对tau纤维的组装和细胞传递 这是许多散发性和遗传性神经退行性疾病的特征。我们的首要假设是 肽N-氨基化的结构特征将使得能够开发选择性靶向 富含β-淀粉样蛋白的褶皱。在目标1中，我们将扩大NAP修饰在追求超稳定b链中的用途 和基于平行B-折叠大环的淀粉样蛋白模拟物。基于NAP的tau模拟物的文库将在 在目标2中合成。将评价这些化合物阻断聚集和细胞增殖的能力。 重组tau纤维以及从AD患者提取的那些纤维的传递。在目标3中，我们将合成一个 一系列抗聚集NAP大环，模拟在致病性tau蛋白中观察到的交叉-b包装 菌株将评估这些蛋白特异性抑制源自于以下的tau原纤维的细胞接种的能力： AD和CBD大脑。我们预计，从这项研究中出现的配体将使一个强大的检查， tau蛋白传播的致病菌株模型。更广泛地说，这些研究将对 设计其它固有地难以靶向的B-折叠和淀粉样蛋白装配的选择性破坏剂。