Single molecules with multi-mechanistic modes of action as probative anti-Alzheimer’s agents

具有多机制作用模式的单分子作为有效的抗阿尔茨海默病药物

基本信息

批准号：
10640255
负责人：
Donald M Sikazwe
金额：
$ 9.93万
依托单位：
UNIVERSITY OF THE INCARNATE WORD
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640255
关键词：
Affinity Alzheimer&apos s Disease Amyloid beta-Protein Analytical Chemistry Animal Disease Models Applications Grants Binding Biological Assay Cause of Death Cessation of life Chemicals Cholinesterase Inhibitors Cholinesterases Clinical Clinical Trials Cognition Cognitive deficits Complex Data Dementia Development Disease Disease Progression Drug Design Endowment Enzyme Inhibition Etiology Evaluation Exhibits Failure Follow-Up Studies Future Glutamates Goals HDAC6 gene Health Health Care Costs Histone Deacetylase Inhibitor Hydroxamic Acids Impaired cognition Impairment In Vitro Individual Isoenzymes Lead Ligands Methods Modification N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurodegenerative Disorders Outcome Pathogenicity Patients Persons Pharmaceutical Preparations Pharmacotherapy Receptor Signaling Reporting Research Second Messenger Systems Series Signal Transduction Structure-Activity Relationship Synthesis Chemistry Techniques Testing Toxic effect antagonist cholinergic clinical efficacy cognitive function design drug development human old age (65+)improved inhibitor innovation meetings multimodality neuron loss novel novel therapeutics palliative pharmacologic poor health outcome radioligand receptor receptor binding repaired screening sigma receptors sigma-2 receptor single molecule small molecule statistics tau Proteins

项目摘要

Project Summary/Abstract Per 2019 Alzheimer’s report, Alzheimer’s disease (AD) dire statistics include: a current patient load of 5.8 million that is projected to expand to 14 million by 2050 in the US, increases in deaths by 145% (per 2000-2017 data), and climbing healthcare costs - $290 billion in 2019. In terms of pharmacotherapy, five clinical drugs [i.e., three cholinesterase inhibitors (ChEIs), one N-methyl-D-aspartate receptor antagonist (NMDRA), and one ChEI/NMDRA combo-drug] are indicated for AD and these drugs only provide symptomatic relief - they do not slow disease progression. A triad of poor health outcomes, lack of effective drugs, and high failure rates of pipeline molecules in clinical trials has therefore increased the urgency to discover more robust anti-AD molecules with novel mechanisms for slowing disease progression. The overall objective of this grant application is to 1) synthesize derivatives of Tubastatin A (a highly selective HDA6 inhibitor, IC50 = 15 nM), 2) evaluate each derivative for binding/functional activities at individual sigma (σ) receptors, and 3) determine each compound’s ability to inhibit histone deacetylase-6 (HDAC6). Central hypothesis: single molecules designed using the multi-target-directed ligands (MTDL) paradigm could more effectively mitigate AD’s neurodegenerative pathogenic cascades and repair cognitive deficits. Evidently, in AD animal models, independent σ-1 activation or σ-2 blockade or HDAC6 inhibition commonly result in decreased neurodegeneration and improved cognitive function. Therefore, our synthesized derivatives are expected to exhibit a de-novo σ-1/HDAC6 or σ- 2/HDAC6 combo-mechanistic anti-neurodegenerative approach towards slowing AD progression or potentially modifying the disease.

项目摘要/摘要根据2019年阿尔茨海默氏症的报告，阿尔茨海默氏病（AD）可怕统计包括：当前患者负载 580万个预计到2050年到2050年将达到1400万，死亡人数增加了145％ 2000-2017数据）和攀登医疗保健费用 - 2019年2900亿美元。就药物治疗而言，五个临床药物[即三种胆碱酯酶抑制剂（CHEI），一种N-甲基-D-天冬氨酸受体拮抗剂（NMDRA）和一个CHEI/NMDRA组合毒品]用于AD AD这些药物仅提供有症状的缓解 - 它们不会慢慢慢慢疾病的进展。有效的药物和临床中管道分子的高衰竭率增加了您迫切需要发现更强大的抗AD分子，并具有减慢疾病的机制进展。（高度选择性的HDA6抑制剂，IC50 = 15 nm），2）评估每个衍生物的结合/功能单个Sigma（σ）受体的活动，以及3）确定每个组合在Hittone中的能力 Deacelase-6（HDAC6）。配体（MTDL）范式可以更有效地减轻AD的神经退行性致病性级联反应并在AD动物模型中修复认知缺陷。封锁或HDAC6抑制通常会导致神经退行性降低并改善认知能力函数。 2/hDAC6组合机械抗神经退行性方法，以减慢广告进度或潜在地改变了疾病。