Gamma-AApeptides as novel biomaterials inhibiting Abeta peptide aggregation

γ-A肽作为抑制Abeta肽聚集的新型生物材料

• 批准号: 9552036
• 负责人: CHUANHAI CAO
• 金额: $ 36.2万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552036
• 关键词: Adverse effects; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid Proteins; Amyloid beta-Protein; Amyloidosis; Binding; Biocompatible Materials; Biological Assay; Biological Markers; Brain; Cells; Chemicals; Dementia; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Early Diagnosis; Eligibility Determination; Enzyme Inhibitor Drugs; Etiology; Excision; Generations; Goals; Human; Huntington Disease; Hydrophobicity; In Vitro; Intervention; Investigation; Lead; Libraries; Ligands; Molecular; Nature; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Peptide Hydrolases; Peptides; Periodicity; Physiological; Plague; Play; Prevention; Production; Research; Role; Signal Pathway; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Mice; Work; abeta accumulation; abeta oligomer; abeta toxicity; aging population; alpha synuclein; base; combinatorial; cross reactivity; cytotoxicity; design; disease diagnosis; disorder prevention; effective therapy; functional group; in vivo; innovation; insight; islet amyloid polypeptide; mouse model; neuroblastoma cell; novel; novel therapeutic intervention; novel therapeutics; peptidomimetics; prevent; protein aggregate; screening; tau Proteins; virtual

Alzheimer's disease (AD) is the most common form and devastating dementia. There are no effective approaches to specifically target and prevent AD pathogenesis. It is accepted that aggregated fibrillar forms of Aβ peptides are prominent hallmarks and the major cause of AD due to their toxicity to neurons. As such, Aβ aggregates are the potential targets for the intervention of AD, as targeting and removal of Aβ fibrils or plaques is expected to eliminate the toxicity of Aβ aggregates. Although the KLVFF peptide has been served as the major lead to develop potential probes to target Aβ aggregation, it only weakly recognizes and inhibits Aβ aggregation. Meanwhile, it is also susceptible to protease degradation. We recently developed a novel one-bead one-compound (OBOC) combinatorial library, from which we identified a potent peptidomimetic that is 100-fold more effective than KLVFF in disrupting Aβ aggregation in vitro. This peptide material also removes the cytotoxicity of Aβ aggregates towards N2a neuro-blastoma cells. Furthermore, this lead compound and its derivative can even significantly remove Aβ plague deposited in the brain of the AD transgenic mice ex vivo. As such, our long-term goal is to develop novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, is to advance our preliminary work by developing new OBOC libraries with enhanced chemodiversity and novel structural classes, so as to identify and develop more potent and effective AApeptide biomaterials that can target and inhibit fibrillar formation of Aβ both in vitro and in vivo. We will first design and synthesize new OBOC gamma- AApeptide libraries with diverse functional groups and constraints by using a range of novel chemical approaches. Then we will use established screening assay to identify and optimize ligands that target and inhibit the aggregation of Aβ peptides. The compounds with activity equivalent or better than the lead compound identified from the preliminary study will be used to study their ability to inhibit Aβ aggregation both in vitro and in vivo on AD-transgenic mice. The proposed study is significant because there is no effective approaches for AD diagnosis and prevention. Our research will provide novel biomaterials to unravel AD pathogenies and to develop potential therapeutic agents for cure of AD. The proposed research is innovative because we not only provide a general approach for the development of novel class of biomaterials specially targeting Aβ aggregates, in addition, this combinatorial approach can be easily extended to identify new materials targeting other amyloid diseases such as Huntington's disease and diabetes diseases.

阿尔茨海默病(AD)是最常见的痴呆症，也是毁灭性的痴呆症。没有 针对和预防AD发病机制的有效途径。这是公认的 聚集的纤维状Aβ多肽是AD的显著特征和主要原因 它们对神经元的毒性。因此，Aβ聚集体是干预的潜在目标 对于AD，靶向和去除Aβ纤维或斑块有望消除Aβ的毒性 集合体。尽管KLVFF多肽已被认为是开发潜力的主要先导 以Aβ聚集为靶标的探针，只能微弱地识别和抑制Aβ聚集。 同时，它也容易被蛋白酶降解。 我们最近开发了一个新的一珠一化合物(OBOC)组合文库，从 我们发现了一种强效的多肽类药物，其效果是KLVFF的100倍 在体外破坏β聚集。这种多肽材料还可以去除β的细胞毒性 向N2a神经母细胞瘤细胞聚集。此外，这种先导化合物和它的 衍生物甚至可以显著消除AD转基因鼠脑内沉积的β鼠疫 小鼠体外实验。因此，我们的长期目标是开发新型生物材料，以防止、阻止 并治愈AD。这项提议目的是通过制定 具有增强的化学多样性和新的结构类的新的OBOC文库，从而识别 以及开发更有效、更有效的靶向和抑制纤维的AA多肽生物材料 Aβ在体外和体内的形成。我们将首先设计和合成新的OBOC Gamma- 通过使用一系列新的具有不同功能基团和限制条件的AA肽文库 化学方法。然后我们将使用建立的筛选方法来鉴定和优化 靶向并抑制Aβ多肽聚集的配体。具有活性的化合物 与初步研究中确定的先导化合物相当或更好的化合物将用于 研究它们在体外和体内对AD转基因小鼠抑制Aβ聚集的能力。 这项拟议的研究具有重要意义，因为目前还没有有效的方法来诊断AD 和预防。我们的研究将提供新的生物材料来揭开AD的病因并 开发治疗阿尔茨海默病的潜在药物。建议的研究具有创新性。 因为我们不仅为小说类的发展提供了一个通用的方法 专门针对Aβ聚集体的生物材料，此外，这种组合方法可以 易于扩展以识别针对其他淀粉样变性疾病的新材料，如亨廷顿氏症 疾病和糖尿病。