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

• 批准号: 10172742
• 负责人: Donald M Sikazwe
• 金额: $ 9.66万
• 依托单位: UNIVERSITY OF THE INCARNATE WORD
• 依托单位国家: 美国
• 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/10172742
• 关键词: Affinity; Alzheimer' 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; Enzyme Inhibition; Etiology; Evaluation; Exhibits; Failure; Follow-Up Studies; Future; Glutamates; Goals; HDAC6 gene; Health; Health Care Costs; 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; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Receptor Signaling; Reporting; Research; Second Messenger Systems; Series; Signal Transduction; Structure; Structure-Activity Relationship; Synthesis Chemistry; Techniques; Testing; Toxic effect; Triad Acrylic Resin; cholinergic; clinical efficacy; cognitive function; design; drug development; human old age (65+); improved; inhibitor/antagonist; innovation; meetings; multimodality; neuron loss; novel; novel therapeutics; palliative; radioligand; receptor; receptor binding; repaired; screening; sigma receptors; sigma-2 receptor; single molecule; small molecule; statistics; tau Proteins

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年阿尔茨海默病报告，阿尔茨海默病(AD)可怕的统计数据包括：当前患者负荷 预计到2050年，美国将有580万人死亡，预计将扩大到1400万人，死亡人数增加145%(每 2000-2017年数据)，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，五 临床药物[即三种胆碱酯酶抑制剂(ChEIs)，一种N-甲基-D-天冬氨酸受体拮抗剂 (NMDRA)和一种ChEI/NMDRA组合药物]用于治疗AD，这些药物仅提供 症状缓解--它们不会减缓疾病的进展。健康状况不佳，缺乏 有效的药物，以及临床试验中流水线分子的高失败率因此增加了 迫切需要发现更强大的抗AD分子和新的延缓疾病的机制 进步。这项资助申请的总体目标是：1)合成Tubasatin A的衍生物 (高选择性HDA6抑制剂，IC50=15 NM)，2)评估每个衍生物的结合/功能 个体Sigma(σ)受体的活性，以及3)决定每种化合物抑制组蛋白的能力 脱乙酰酶-6(HDAC6)。中心假设：利用多靶点定向设计的单分子 配体(MTDL)范式可以更有效地缓解AD的神经退行性致病性级联反应 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 阻断或抑制HDAC6通常会导致神经变性减少和认知能力改善 功能。因此，我们合成的衍生物有望表现出从头开始的σ-1/HDAC6或σ- 2/HDAC6联合机制抗神经退行性变方法减缓AD进展或 有可能改变这种疾病。