Recognition of Abeta monomeric helix

Abeta 单体螺旋的识别

• 批准号: 10607926
• 负责人: CHUANHAI CAO
• 金额: $ 57.98万
• 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 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607926
• 关键词: AD transgenic mice; Aducanumab; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer’s disease biomarker; Amyloid Proteins; Amyloid beta-Protein; Amyloidosis; Binding; Biocompatible Materials; Biological Assay; Brain; Cells; Chemicals; Computer Models; Dementia; Dendrites; Deposition; Development; Diabetes Mellitus; Disease; Enzyme Inhibitor Drugs; Equilibrium; Etiology; Excision; FDA approved; Goals; Growth; Huntington Disease; In Vitro; Intervention; Investigation; Kinetics; Lead; Libraries; Memory; Microglia; Molecular Conformation; Molecular Probes; Molecular Weight; Monoclonal Antibodies; Mus; Nature; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peptide Hydrolases; Peptide antibodies; Peptides; Phagocytosis; Physiological; Plague; Play; Predisposition; Prevention; Process; Production; Protocols documentation; Research; Role; Senile Plaques; Series; Side; Signal Pathway; Structure; Surface; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Western Blotting; Work; abeta accumulation; abeta oligomer; alpha synuclein; analog; behavior test; beta pleated sheet; cell growth; cost; cytotoxicity; design; disorder prevention; functional group; improved; in vitro Assay; in vivo; innovation; insight; islet amyloid polypeptide; mimetics; monomer; mouse model; neurodegenerative dementia; neuronal survival; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; peptidomimetics; prevent; protein aggregation; rational design; side effect; tau Proteins; therapeutically effective; virtual

Alzheimer’s disease (AD) is the most devastating dementia causing severe global concern. Although the mechanism of AD pathogenesis is still under debate, it is widely accepted that aggregated fibrillar forms of Aβ peptides are prominent hallmarks and the major cause of AD due to their toxicity to neurons. Therefore, 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 neuronal toxicity of Aβ aggregates. However, eradication of total Aβ peptides by antibodies such as the new drug aducanumab could lead to severe side effects, whereas anti-Aβ aggregation by β-sheet mimetics could only prevent or delay the process of aggregation process and could not disrupt the formed/existing Aβ aggregation. Therefore, development of more effective molecular probes that not only prevent but also disrupt Aβ fibril formation is still in an urgent need. In contrast to the use of β-sheet mimetics to block Aβ fibrillar growth, recently we designed a series of helical peptidomimetics that can tightly bind and stabilize monomeric helical Aβ and thereby shifting the equilibrium of Aβ conformation into off-pathway structure, leading to both potent prevention and disruption of Aβ aggregation, as well as significant enhancement of neuro cell growth and dendrite branching without virtually any cytotoxicity. Furthermore, this lead compound could remove Aβ plague deposited in the brain of the AD transgenic mouse and completely recover the memory of mice in the behavior test. As such, our long-term goal is to develop novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, which is the first step to achieve the long-term goal, is to advance our preliminary work by rationally designing structurally related analogues of the current lead, so as to identify and develop more potent and effective compounds that can tightly bind and stabilize Aβ monomer and thus prevent and disrupt Aβ aggregation both in vitro and in vivo. We will first design helical peptidic foldamer bearing diverse functional groups and closely mimic the binding pattern of our lead compound. Then we will use our established in vitro assays such as 2D-NMR and kinetic binding assays to identify and optimize our designed compounds that target and inhibit the aggregation of Aβ peptides. The compounds with activity equivalent or better than the lead compound will be used to study their ability to inhibit Aβ aggregation both in vitro and in vivo in AD-transgenic mice. The proposed study is significant because there is no effective therapeutic strategy for AD diagnosis and prevention. Our research will provide molecules with novel mechanism to unravel AD pathogenies and to develop potential molecular probes and therapeutic agents for cure of AD. The proposed research is innovative because we not only provide a new strategy for the development of novel class of foldameric prevent and disrupt Aβ aggregation, in addition, this approach of rational design for the recognition of Aβ surface 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（Alzheimer's disease，AD）是引起全球严重关注的最具破坏性的痴呆症。虽然 AD发病机制仍存在争议，但广泛认为Aβ的聚集纤维形式 肽由于其对神经元的毒性是AD的突出标志和主要原因。因此，Aβ 聚集体是AD干预的潜在靶点，如靶向和去除Aβ纤维或斑块 有望消除Aβ聚集体的神经元毒性。然而，通过以下方法根除总Aβ肽， 新药aducanumab等抗体可能导致严重的副作用，而抗A β聚集 β-折叠模拟物只能阻止或延迟聚集过程的过程，而不能破坏聚集过程。 形成/存在Aβ聚集。因此，开发更有效的分子探针，不仅可以防止 而且还能破坏Aβ原纤维的形成。 与使用β-折叠模拟物阻断Aβ纤维生长相反，最近我们设计了一系列螺旋状的 肽模拟物，可以紧密结合和稳定单体螺旋Aβ，从而改变 Aβ构象转变为非途径结构，从而有效预防和破坏Aβ聚集， 以及显著增强神经细胞生长和树突分支而几乎没有任何细胞毒性。 此外，该先导化合物还能清除AD转基因小鼠脑内沉积的Aβ斑 并在行为学试验中完全恢复小鼠的记忆。因此，我们的长期目标是发展 新的生物材料，可以预防，停止和治疗AD。这项建议的目的是， 实现长远目标，是通过合理设计结构相关的前期工作， 目前的铅类似物，以确定和开发更有力和有效的化合物，可以紧密地 结合并稳定Aβ单体，从而在体外和体内防止和破坏Aβ聚集。我们将 首先设计具有不同官能团的螺旋肽折叠体，并紧密模拟 我们的先导化合物然后，我们将使用我们建立的体外试验，如2D-NMR和动力学结合试验 鉴定和优化我们设计的靶向和抑制Aβ肽聚集的化合物。的 将使用活性等同于或优于先导化合物的化合物来研究它们抑制 AD转基因小鼠体内和体外的Aβ聚集。 这项研究是有意义的，因为目前还没有有效的治疗策略用于AD的诊断， 预防我们的研究将提供新的分子机制，以解开AD的病因，并开发 为AD的治疗提供潜在的分子探针和治疗药物。拟议的研究具有创新性，因为 我们不仅为开发新型折叠体预防和阻断Aβ提供了新的策略， 此外，这种理性设计的方法对于Aβ表面的识别也很容易推广 以鉴定针对其他淀粉样疾病如亨廷顿病和糖尿病的新材料。