Gamma-AApeptides as novel biomaterials inhibiting Abeta peptide aggregation

阿尔茨海默病（AD）是最常见的形式和破坏性痴呆。没有 有效的方法，具体针对和预防AD发病机制。我同意 Aβ肽的聚集纤维形式是AD的突出标志和主要原因， 对神经元的毒性。因此，Aβ聚集体是干预的潜在靶点 由于靶向和去除Aβ纤维或斑块有望消除Aβ的毒性， 集料.虽然KLVFF肽已被作为开发潜力的主要先导， 作为靶向Aβ聚集的探针，它仅微弱地识别和抑制Aβ聚集。 同时，它也容易被蛋白酶降解。 我们最近开发了一种新的单珠单化合物（OBOC）组合文库， 我们发现了一种有效的肽模拟物，其在治疗糖尿病中的作用比KLVFF有效100倍。 在体外破坏Aβ聚集。这种肽材料还能去除Aβ的细胞毒性 向N2 a神经母细胞瘤细胞聚集。此外，该先导化合物及其 衍生物甚至可以显著清除AD转基因小鼠脑内沉积的Aβ斑 离体小鼠。因此，我们的长期目标是开发新型生物材料， 治愈AD。本提案的目的是通过制定 具有增强的化学多样性和新的结构类别的新的OBOC文库，以便鉴定 并开发出更有效的AA肽生物材料，可以靶向和抑制纤维化， Aβ在体内和体外的形成。我们将首先设计和合成新的OBOC γ- 通过使用一系列新颖的方法， 化学方法。然后，我们将使用已建立的筛选试验，以确定和优化 靶向和抑制Aβ肽聚集的配体。活性化合物 将使用与初步研究中确定的先导化合物等同或更好的化合物， 研究它们在体外和体内在AD转基因小鼠上抑制Aβ聚集的能力。 由于目前尚无有效的AD诊断方法，因此本研究具有重要意义 和预防我们的研究将提供新的生物材料，以解开AD的病因， 开发治疗AD的潜在药物。该研究具有创新性 因为我们不仅提供了一个一般的方法，为发展新的类， 生物材料专门针对Aβ聚集体，此外，这种组合方法可以 很容易扩展到识别针对其他淀粉样疾病的新材料，如亨廷顿病 疾病和糖尿病。

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.