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.

小分子药物治疗阿尔茨海默病 总结： 阿尔茨海默病（AD）是一种进行性和致命的神经系统疾病，影响大约一个- 占65岁以上人口的十分之一。目前没有治愈这种疾病的方法。病理 该疾病的特征包括β-淀粉样蛋白（AAPs）在脑中的形成和积累。早些时候 通过直接靶向β-或γ-分泌酶的催化活性来降低总腺苷酸的治疗尝试， 因为酶水解APP以外的其他底物，许多具有关键的细胞功能，所以不成功。 Cenna有一种不针对分泌酶的新技术， 来自早老素（PS-1）的氨基末端结构域的肽药物候选物P8和P4，具有 以抑制体外和AD转基因（Tg）小鼠模型中的ApoA产生。我们最近 提供了证据（1）肽P4和P8与蛋白质产生强的、特异性的和生物学相关的结合， APP 695的纯化胞外域。我们进一步证明，肽对A12的还原不 影响β-或γ-分泌酶的催化活性或APP的水平。这些肽及其衍生物提供 治疗AD的新的潜在候选药物。虽然P8正在进一步开发为肽药物， P4太不稳定了重要的是，除P8外，还应培养其他后备候选人。这将是 有利的是鉴定在与P4和P8相同的位点结合APP的小分子化合物， 同时也降低了血压。我们进行了分子模拟研究，以确定APP上的结合位点 P4和P8的胞外域。完成这一点后，我们实际上筛选了一个电子化合物库， 鉴定那些被预测与APP上与P4和P8相同的位点结合的分子。的 筛选了约160，000个结构，总共249个结构表明在P4或P8结合位点与APP结合。 这些化合物已被评分并分组。在目前的赠款申请中，我们的具体目标是：1） 通过微阵列分析，实验证实了小的 通过虚拟筛选鉴定分子化合物。2)为了测试小分子化合物 对于它们在体外减少Aβ产生的能力给出阳性命中，和3）为了在APP Tg小鼠中进行体内测试， 在体外鉴定的所选化合物以与P4和P8相似的量降低Aβ。 该项目的成功完成将为我们提供小分子候选人， 通过与我们的肽候选物相同的机制在体外和体内抑制。与肽一样， 预期分子化合物不会影响分泌酶的催化活性。此外，委员会认为， 这些化合物可被开发为可穿过血脑屏障的口服药物。