Recognition of Abeta monomeric helix

阿尔茨海默病(AD)是引起全球严重关注的最具破坏性的痴呆症。尽管 AD的发病机制仍在争论中，人们普遍认为聚集的纤维状Aβ 多肽是AD的显著标志，也是AD的主要原因，因为它们对神经元具有毒性。因此，Aβ 聚集体是AD干预的潜在靶点，因为靶向和去除Aβ纤维或斑块 有望消除Aβ聚集体的神经元毒性。然而，通过以下方法消除总Aβ多肽 新药阿杜卡努单抗等抗体可能会导致严重的副作用，而抗Aβ聚集 通过β-Sheet模拟只能阻止或延缓聚集过程，而不能破坏 形成/现有的Aβ聚合。因此，开发更有效的分子探针不仅可以防止 但也扰乱了β原纤维的形成，仍然是一个迫切需要的问题。 与使用β-Sheet模拟物阻止Aβ纤维生长相反，最近我们设计了一系列螺旋 一种能够紧密结合和稳定单体螺旋Aβ从而改变其平衡的多肽类药物 β构象转变为非途径结构，导致有效地防止和破坏Aβ聚集， 以及显著促进神经细胞生长和树突分支，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β鼠疫 并在行为学测试中完全恢复小鼠的记忆。因此，我们的长期目标是发展 可预防、阻止和治愈AD的新型生物材料。这项提案的目标，这是实现 实现长远目标，就是要通过合理设计结构关系来推进前期工作 目前铅的类似物，以便识别和开发更有效的化合物，这些化合物可以紧密地 结合和稳定Aβ单体，从而在体外和体内阻止和破坏Aβ聚集。我们会 首先设计了具有不同功能基团的螺旋多肽折叠体，并紧密模拟了其结合模式 我们的先导化合物。然后我们将使用我们建立的体外分析方法，如2D-核磁共振和动力学结合分析 鉴定和优化我们设计的靶向和抑制Aβ多肽聚集的化合物。这个 活性相当于或高于先导化合物的化合物将被用来研究它们的抑制能力。 AD转基因小鼠体内和体外的β聚集。 这项拟议的研究具有重要意义，因为目前还没有有效的治疗策略来诊断和治疗AD 预防。我们的研究将为揭示AD的致病机制和发展提供新的分子机制 治疗阿尔茨海默病的潜在分子探针和治疗剂。这项拟议的研究具有创新性，因为 我们不仅为开发新型叶状预防和干扰Aβ提供了新的策略 此外，对于β曲面的识别，这种合理设计的方法可以很容易地扩展 识别针对其他淀粉样蛋白疾病的新材料，如亨廷顿病和糖尿病。

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.