Small molecule therapy for Alzheimer's disease

描述（由申请人提供）： 摘要本研究的目的是开发一种有效的治疗阿尔茨海默病（AD）的方法，通过使用能够浓缩、结合和消除淀粉样肽的方法，从而延迟和/或停止斑块在大脑中的沉积。我们先前已经开发并证明了一种排毒凝胶系统，该系统利用逆转肽[ffvlk]在体外和体内螯合A肽。目前的建议是探索和开发来自不同来源的替代小分子来捕获A蛋白。因此，我们建议合成不同版本的新小分子，并检查它们结合A的有效性。根据最近的初步数据，我们预计这些分子可能对A？表现出相似或增加的亲和力。新化合物的功效将通过我们实验室开发的体外模型系统与现有肽进行比较。随后，将在AD模型小鼠中评估小分子的功效。这项提案的目标是建立一个原则性的证明，即替代分子也可以用来结合A，从而增加我们的潜在候选药物的目录。这项研究的结果是创造了一个替代治疗候选人的管道，以从系统中隔离有毒的A肽。开发替代分子变得必要，因为如果需要，它们可以用于联合治疗。此外，候选分子库将有助于在未来的研究中选择副作用和毒性最小的分子。这项研究预计将导致识别新的小分子来治疗AD。 公共卫生相关性：在阿尔茨海默病（AD）中，在大脑中形成复杂的细胞外沉积的淀粉样肽（斑块）。噬斑主要由A <$-40和A <$-42肽聚集体组成。理想的治疗应该能够破坏这种聚集/沉积过程。我们之前已经证明，我们的水凝胶制剂与逆（RI）肽，f-f-v-l-k，螯合A肽在体外和体内，这导致减少斑块形成。这种凝胶在小鼠中的施用改善了记忆相关性。该RI肽具有衍生自A肽的残基16-20的序列。我们现在建议使用一组来自不同来源的不同小分子作为诱饵来捕获有毒的A肽。我们建议以降低抗原性/免疫原性并增加对A？的结合亲合力的方式设计这些分子。长期目标是创建一个有效的小分子治疗剂目录，并进行临床前疗效评估。该提案预计将导致识别出具有上级A ²结合特征的新分子。

DESCRIPTION (provided by applicant): ABSTRACT The objective of our research is to develop an effective therapy for Alzheimer's disease (AD), by using an approach that is able to concentrate, bind and eliminate ¿-amyloid peptides and thereby delay and or halt deposition of plaque in the brain. We have previously developed and demonstrated a detox gel system utilizing a retro-inverse peptide [ffvlk] to sequester A¿ peptides, in vitro and in vivo. The current proposal is to explore and develop alternate small molecules derived from diverse sources to capture A¿ proteins. Therefore, we propose to synthesize different versions of new small molecules and examine their validity to bind A¿. We anticipate that these molecules are likely to exhibit similar or increased affinity for A¿ based on recent preliminary data. Efficacy of the new compounds will be compared with the existing peptide by an in vitro model system developed in our laboratory. Following this, efficacy of the small molecules will be evaluated in AD model mice. The goal of this proposal is to establish proof- of-principle that alternate molecules can also be used to bind A¿ thus increasing our catalog of potential drug candidates. The outcome of this research is the creation of a pipeline of alternate therapeutic candidates to sequester toxic A¿ peptides from the system. Development of alternate molecules becomes necessary as they can be used for a combination therapy, if needed. Besides, repertoire of candidate molecules will be useful to pick the ones with least side effects and toxicity in future studies. This study is expected to result in the identification of novel small molecules to treat AD. PUBLIC HEALTH RELEVANCE: In Alzheimer's disease (AD), complex extra cellular deposition of ¿ -amyloid peptides (plaques) are formed in the brain. Plaques are mainly composed of A¿-40 and A¿-42 peptide aggregates. The ideal therapeutic should be able to disrupt this aggregation/deposition process. We have previously demonstrated that our hydrogel formulation with a retro-inverse (RI) peptide, f-f-v-l-k, sequesters A¿ peptides in vitro and in vivo, which leads to decreased plaque formation. Administration of this gel in mice improved memory correlates. This RI peptide has its sequence derived from the residues 16-20 of the A¿ peptide. We now propose to use a different set of small molecules derived from diverse sources as bait to capture the toxic A¿ peptides. We propose to design these molecules in a way that they have decreased antigenicity /immunogenicity and increased binding avidity to A¿. The long-term goal is to create a catalog of effective small molecule therapeutics and perform preclinical efficacy evaluation. The proposal is expected to result in the identification of new molecules with superior A¿ binding characteristics.