Small molecule therapeutics for Alzheimer's Disease

阿尔茨海默病的小分子疗法

• 批准号: 9253281
• 负责人: NAZNEEN N DEWJI
• 金额: $ 22.5万
• 依托单位: CENNA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253281
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Applications Grants; Back; Binding; Binding Sites; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cell physiology; Cells; Computer Assisted; Confocal Microscopy; Development; Disease; Drug Kinetics; Elderly; Enzymes; Gastrointestinal tract structure; Goals; In Vitro; Interferometry; Libraries; Microarray Analysis; Modification; Molecular Models; N-terminal; Oral; Peptides; Pharmaceutical Preparations; Population; Production; Site; Structure; Testing; Therapeutic; Transgenic Mice; Water; Work; base; drug candidate; gamma secretase; in vivo; molecular modeling; mouse model; nervous system disorder; new technology; novel strategies; peptide drug; presenilin; presenilin-1; prevent; programs; screening; secretase; small molecule; small molecule therapeutics; virtual

SMALL MOLECULE THERAPEUTICS FOR ALZHEIMER'S DISEASE SUMMARY: Alzheimer's disease (AD) is a progressive and fatal neurological disorder that affects approximately one- tenth of the population over the age of 65. There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of ß-amyloid (Aß). Earlier therapeutic attempts at lowering total Aß by directly targeting the catalytic activities of ß- or γ-secretase were unsuccessful as the enzymes hydrolyze other substrates besides APP, many with critical cellular functions. Cenna has a novel technology that does not target the secretases, which has yielded two potential peptide drug candidates P8 and P4 from the amino terminal domain of Presenilin (PS-1), with the ability to inhibit the production of Aß in vitro and in a transgenic (Tg) mouse model of AD. We recently provided evidence (1) that peptides P4 and P8 give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. We further demonstrated that the reduction of Aß by the peptides does not affect the catalytic activities of ß- or γ-secretase, or the level of APP. These peptides and their derivatives offer new potential drug candidates for the treatment of AD. While P8 is being further developed as a peptide drug, P4 is too unstable. It is important to develop alternate back-up candidates besides P8. It would be advantageous to identify small molecule compounds that bind APP at the same sites as P4 and P8 and by so doing also reduce Aß. We have carried out molecular modeling studies to determine binding sites on the APP ectodomain for both P4 and P8. Having accomplished that, we virtually screened a library of e-compounds to identify those molecules that would be predicted to bind the same sites on APP as P4 and P8. Of the ~160,000 structures screened, a total of 249 suggested binding to APP at either the P4 or P8 binding site. These compound have been scored and grouped. In the current grant application our specific aims are: 1) To experimentally confirm by microarray analysis the binding to the APP ectodomain of the small molecule compounds identified by virtual screening. 2) To test the small molecule compounds that give positive hits for their ability to reduce Aβ production in vitro and 3) To test in vivo in APP Tg mice, selected compounds identified in vitro to reduce Aβ by similar amounts as P4 and P8. A successful completion of the project will provide us with small molecule candidates with the ability to reduce Aß in vitro and in vivo by the same mechanism as our peptide candidates. As with the peptides, the small molecule compounds would not be expected to affect the catalytic activities of the secretases. Furthermore, these compounds may be developed as oral drugs that can cross the blood brain barrier.

小分子疗法用于阿尔茨海默氏病 概括： 阿尔茨海默氏病（AD）是一种进行性和致命的神经系统疾病，影响了大约1- 65岁以上人口的十分之一。 β-淀粉样蛋白（Aß）的形成和积累的标志 通过直接针对的催化活性来降低总Aß的治疗尝试 除了应用程序以外，许多酶水解了其他底物，许多具有关键的细胞功能。 Cenna具有一种新技术，该技术不针对Secralasses，这产生了两个潜力 来自Presenilin（PS-1）的肽药物候选P8和P4，具有能力 在AD的AD中，抑制体外和转基因（TG）小鼠模型的产生 有证据的证据（1）表明肽P4和P8具有强，特异性和生物学相关的结合。 App 695的纯化外生域。我们进一步证明了肽对Aß的减少不可能 影响β或γ-分泌酶的催化活性，或APP的水平。 P8的新型药物治疗时，正在进一步发展为肽药物 P4太不稳定了 有利地识别在同一绑定应用程序的小分子化合物位于p4和p8和p8和byso 这样做也可以减少Aß。 P4和P8的ectodomain已完成。 识别那些将与您的P4和P8上相同位点结合的分子 〜160,000个结构，在P4或P8绑定位点上为App的249个aotal。 这些化合物已在当前的赠款应用中进行了分组。 通过微阵列分析确认实验确认与小型应用的结合 通过虚拟筛选确定的分子化合物。 为减少体外生产和3）在App TG小鼠中进行体内测试，给予降低的积极命中。 选定的化合物在体外鉴定出与P4和P8相似的Aβ。 成功压缩了该项目，为我们提供了小分子候选物，能够减少 通过与我们的肽候选物相同的机制，体外和体内Aß。 不会期望分子化合物会影响尿布酶的催化性。 这些化合物可以作为跨越血脑屏障的口服药物开发。