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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.

项目总结/摘要根据2019年阿尔茨海默病报告，阿尔茨海默病（AD）可怕的统计数据包括： 5.8预计到2050年，美国的死亡人数将增加145%（每 2000-2017年的数据），以及不断攀升的医疗成本-2019年为2900亿美元。在药物治疗方面，5 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（匪R）和一种ChEI/匪R组合药物]适用于AD，这些药物仅提供症状缓解-它们不会减缓疾病进展。健康状况不佳、缺乏有效的药物，和管道分子在临床试验中的高失败率，因此增加了迫切需要发现具有减缓疾病的新机制的更强大的抗AD分子进展本基金申请的总体目标是：1）合成Tubastatin A的衍生物（高选择性HDA 6抑制剂，IC 50 = 15 nM），2）评价每种衍生物的结合/功能对单个σ（σ）受体的活性，和3）确定每种化合物抑制组蛋白的能力脱乙酰酶-6（HDAC 6）。中心假设：使用多靶点定向设计的单分子 MTDL范式可以更有效地减轻AD的神经退行性致病级联反应修复认知缺陷显然，在AD动物模型中，独立的σ-1激活或σ-2激活是可能的。阻断或HDAC 6抑制通常导致神经变性减少和认知功能改善。功能因此，我们合成的衍生物预期表现出从头σ-1/HDAC 6或σ- 2/HDAC 6联合机制抗神经退行性方法减缓AD进展或有可能改变疾病