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:
- 金额:$ 9.93万
- 依托单位:
- 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:
- 关键词:AffinityAlzheimer&aposs DiseaseAmyloid beta-ProteinAnalytical ChemistryAnimal Disease ModelsApplications GrantsBindingBiological AssayCause of DeathCessation of lifeChemicalsCholinesterase InhibitorsCholinesterasesClinicalClinical TrialsCognitionCognitive deficitsComplexDataDementiaDevelopmentDiseaseDisease ProgressionDrug DesignEndowmentEnzyme InhibitionEtiologyEvaluationExhibitsFailureFollow-Up StudiesFutureGlutamatesGoalsHDAC6 geneHealthHealth Care CostsHistone Deacetylase InhibitorHydroxamic AcidsImpaired cognitionImpairmentIn VitroIndividualIsoenzymesLeadLigandsMethodsModificationN-Methyl-D-Aspartate ReceptorsNerve DegenerationNeurodegenerative DisordersOutcomePathogenicityPatientsPersonsPharmaceutical PreparationsPharmacotherapyReceptor SignalingReportingResearchSecond Messenger SystemsSeriesSignal TransductionStructure-Activity RelationshipSynthesis ChemistryTechniquesTestingToxic effectantagonistcholinergicclinical efficacycognitive functiondesigndrug developmenthuman old age (65+)improvedinhibitorinnovationmeetingsmultimodalityneuron lossnovelnovel therapeuticspalliativepharmacologicpoor health outcomeradioligandreceptorreceptor bindingrepairedscreeningsigma receptorssigma-2 receptorsingle moleculesmall moleculestatisticstau 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
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations.
- DOI:10.3390/molecules28104191
- 发表时间:2023-05-19
- 期刊:
- 影响因子:0
- 作者:Nguyen N;Lewis A;Pham T;Sikazwe D;Cheng KH
- 通讯作者:Cheng KH
Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities.
苯乙酰基/trolox-酰胺:合成,Sigma-1,HDAC-6和抗氧化活性。
- DOI:10.3390/ijms242015295
- 发表时间:2023-10-18
- 期刊:
- 影响因子:5.6
- 作者:Flores R;Iqbal S;Sikazwe D
- 通讯作者:Sikazwe D
Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands.
作为潜在 σ1R 配体的新型酰基脲类似物的设计和合成。
- DOI:10.3390/molecules28052319
- 发表时间:2023-03-02
- 期刊:
- 影响因子:0
- 作者:Thapa R;Flores R;Cheng KH;Mochona B;Sikazwe D
- 通讯作者:Sikazwe D
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Donald M Sikazwe其他文献
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{{ truncateString('Donald M Sikazwe', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 9.93万 - 项目类别:
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:
10430206 - 财政年份:2021
- 资助金额:
$ 9.93万 - 项目类别: