Small molecule therapy for Alzheimer's disease

阿尔茨海默病的小分子疗法

• 批准号: 7802449
• 负责人: PAZHANI SUNDARAM
• 金额: $ 27.49万
• 依托单位: RECOMBINANT TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802449
• 关键词: Adverse effects; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid deposition; Avidity; Binding; Biological Models; Brain; Cataloging; Catalogs; Characteristics; Combined Modality Therapy; Complex; Data; Deposition; Detox; Development; Dissociation; Dominant-Negative Mutation; Drug Formulations; Effectiveness; Exhibits; Future; Gel; Goals; Hydrogels; In Vitro; Indium; Individual; Laboratories; Lead; Lesion; Memory; Methods; Mus; Outcomes Research; Parents; Peptides; Polyethylene Glycols; Process; Property; Proteins; Research; Retro-Inverso Peptide; Safety; Source; Staging; System; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Variant; abstracting; amyloid peptide; base; brain circulation; combat; comparative efficacy; design; drug candidate; effective therapy; efficacy evaluation; efficacy testing; enantiomer; experience; immunogenicity; improved; in vitro Model; in vivo; inhibitor/antagonist; mouse model; novel; pharmacophore; pre-clinical; preclinical efficacy; prevent; public health relevance; research study; small molecule; synthetic peptide

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.

描述（由申请人提供）： 摘要 我们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，通过使用一种能够浓缩、结合和消除β-淀粉样肽的方法，从而延迟和/或阻止斑块在大脑中的沉积。我们之前开发并展示了一种排毒凝胶系统，利用逆向反向肽 [ffvlk] 在体外和体内隔离 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与 A¿ 结合的有效性。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。该提案的目标是建立原理验证，即替代分子也可用于结合 A¿，从而增加我们的潜在候选药物目录。这项研究的成果是创建了一系列替代治疗候选药物，以隔离系统中的有毒 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。这项研究预计将鉴定出治疗 AD 的新型小分子。 公共健康相关性：在阿尔茨海默病 (AD) 中，大脑中会形成复杂的 β-淀粉样肽（斑块）细胞外沉积。斑块主要由 A¿-40 和 A¿-42 肽聚集体组成。理想的治疗方法应该能够破坏这种聚集/沉积过程。我们之前已经证明，我们的水凝胶配方含有逆向反向（RI）肽，f-f-v-l-k，在体外和体内隔离A¿肽，从而减少斑块形成。给小鼠注射这种凝胶可以改善记忆相关性。该 RI 肽的序列源自 A¿ 肽的残基 16-20。我们现在建议使用一组不同来源的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/免疫原性和增加与 A¿ 的结合亲和力的方式设计这些分子。长期目标是创建有效的小分子治疗药物目录并进行临床前疗效评估。该提案预计将鉴定出具有优异 A¿ 结合特性的新分子。