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。目前尚无治愈这种疾病。病理 该疾病的标志包括β-淀粉样蛋白（Aß）大脑中的形成和积累。较早 通过直接靶向β-或γ-分泌酶的催化活性来降低总Aß的治疗尝试是 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具有一种新的技术，该技术不针对分泌酶，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 为了抑制AUD AD的AD和转基因（TG）小鼠模型的Aß产生。我们最近 提供的证据（1）表明P4和P8具有与 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ß-或γ-分泌酶或APP水平的催化活性。这些肽及其衍生物提供 用于治疗AD的新潜在候选药物。当P8作为肽药物进一步开发 P4太不稳定了。除了P8以外，还要开发替代备用候选者很重要。这将是 有利于识别与P4和P8在同一位点结合应用的小分子化合物，因此 这样做也减少了Aß。我们已经进行了分子建模研究，以确定应用程序上的结合位点 P4和P8的胞外域。实现了这一目标后，我们实际上将电子混合物库筛选到 识别那些将预测将在APP上与P4和P8相同的位点结合的分子。的 约有160,000个结构进行了筛选，共有249个建议在P4或P8结合位点与APP结合。 这些化合物已被评分和分组。在当前的赠款应用程序中，我们的具体目的是：1） 通过微阵列分析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。 2）测试小分子化合物 在体外降低Aβ产生的能力和3）在App TG小鼠中测试体内测试的能力，给予积极的命中。 选定的化合物在体外鉴定出与P4和P8相似的Aβ。 该项目的成功完成将为我们提供小分子候选者，能够减少 通过与我们的肽候选物相同的机制在体外和体内Aß。与宠物一样，小 不会期望分子化合物会影响分泌酶的催化活性。此外， 这些化合物可以作为可以越过血脑屏障的口服药物开发。