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）： 摘要我们的研究目的是通过使用能够集中，结合和消除„ - 淀粉样辣椒的方法来为阿尔茨海默氏病（AD）开发有效的治疗疗法，从而延迟大脑中斑块的沉积。我们以前曾使用复古肽[FFVLK]开发并证明了排毒凝胶系统，以隔离体外和体内肽。当前的建议是探索和开发源自潜水员来源的替代小分子以捕获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。我们预计，基于最近的初步数据，这些分子可能会退出类似或增加的对A的亲和力。新化合物的功效将与我们实验室中开发的体外模型系统与现有肽进行比较。此后，将在AD模型小鼠中评估小分子的效率。该提案的目的是建立原则上的证明，即替代分子也可以用来结合我们增加潜在药物候选物的目录。这项研究的结果是创建了替代治疗候选物的管道，以隔离系统中有毒肽。有必要开发替代分子，因为它们可以用于组合治疗（如果需要）。此外，候选分子的曲目对于在未来的研究中选择副作用和毒性最少的候选分子将是有用的。预计这项研究将导致鉴定出新的小分子以治疗AD。 公共卫生相关性：在阿尔茨海默氏病（AD）中，大脑中形成了复杂的 - 淀粉样肽（斑块）的复杂额外的细胞沉积。斑块主要由a - -40和a。-42肽聚集体组成。理想的疗法应该能够破坏这种聚合/沉积过程。我们先前已经证明了具有恢复（RI）肽F-F-V-L-K的水凝胶配方，在体外和体内会延迟A肽，从而导致斑块形成改善。在小鼠中的这种凝胶的给药可改善记忆力相关。这种Ri Pepperide的序列源自A肽的16-20残留物。现在，我们建议使用源自潜水员来源的不同小分子作为诱饵来捕获有毒的肽。我们建议以一种改善抗原性 /免疫原性并增加与A的结合相对的方式设计这些分子。长期目标是创建有效的小分子治疗目录并进行临床前有效性评估。该建议有望导致具有优质特征的新分子鉴定。