Novel bivalent multifunctional ligands towards Alzheimer's disease

针对阿尔茨海默病的新型二价多功能配体

• 批准号: 8372880
• 负责人: Shijun Zhang
• 金额: $ 30.65万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372880
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Antioxidants; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Cholesterol; Clinical Trials; Cognition; Curcumin; Dementia; Development; Exhibits; FDA approved; Goals; Human; Impairment; In Vitro; Intervention; Laboratories; Lead; Length; Ligands; Link; Medical Economics; Membrane Microdomains; Memory; Metals; Modification; Molecular; Mus; Nature; Neuroblastoma; Neurodegenerative Disorders; Neurons; Outcome Study; Oxidative Stress; Pathogenesis; Pathology; Patients; Peptides; Pharmacotherapy; Process; Property; Public Health; Research; Risk Factors; Role; Selection Criteria; Series; Societies; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Trace Elements; Transgenic Organisms; base; cytotoxicity; design; immunocytochemistry; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; mouse model; neuroinflammation; neuroprotection; novel; novel strategies; preclinical study; small molecule; social; tool

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia. Emerging evidence has recognized small, soluble oligomers of amyloid-¿-peptide (A¿Os) as the major toxic species for cognition impairment in AD. Furthermore, evidence has been accumulating that oxidative stress, biometal dyshomeostasis, and neuroinflammation may also contribute to the pathology of AD. Numerous small molecules targeting each of these risk factors have been developed and tested in preclinical and clinical trials, however, none of them has been approved by FDA as AD-modifying agents. This may suggest that one of the alternative and promising strategies is to use multifunctional ligands to tackle these risk factors simultaneously. Furthermore, evidence has increasingly underscored the important roles of cell membrane/lipid rafts (CM/LR) in the pathology of AD and CM/LR have been implicated to associate with all the identified risk factors in AD. This indicates that this relationship can be exploited therapeutically to develop strategic distinct multifunctional agents by incorporating this factor into molecular design. The overall goa of this proposal is to validate and develop more potent bivalent multifunctional A¿ oligomerization inhibitors (BMAOIs) that contain a multifunctional A¿O-inhibitor with intrinsic antioxidant/metal chelating functions and a CM/LR anchor moiety as lead compounds for further preclinical studies. The central hypothesis of this application is that these BMAOIs will anchor the multifunctional A¿O-inhibitor moiety inside, or in the vicinity of, CM/LR where A¿ oligomerization, Ab/biometal interactions, and oxidative stress occur to increase its local concentration and accessibility, thus enhancing its efficiency. Preliminary studies in our laboratory have reached the proof-of- concept of the BMAOIs strategy and resulted in the identification of two promising lead compounds for further optimization. Three specific aims are proposed to achieve our objective in this application. In aim 1, a series of BMAOIs will be designed and synthesized based on the newly identified lead compounds to modify and optimize the spacer domain, CM/LR anchor domain and A¿O-inhibitor domain. In aim 2, the designed BMAOIs will be evaluated in various in vitro assays including inhibition of A¿O formation in association with protective activity in human neuroblastoma MC65 cells as well as neuroprotective effects on differentiated SH-SY5Y and mouse primary neurons. The co-localization of BMAOIs with CM/LR will also be investigated in MC65 cells and mouse primary neurons. In addition, antioxidant and metal complexation properties of selected BMAOIs will be tested. In aim 3, potent BMAOIs that passed the selection criteria of aim 2 will be evaluated for their effects on cognition and A¿ pathology in transgenic TgCRND8 mice. The proposed research is innovative because we seek a new class of BMAOIs targeting A¿Os, oxidative stress, A¿/biometal interactions and CM/LR as novel pharmacological tools and potential AD-modifying agents. The outcome of this study would be a novel, validated, BMAOIs strategy available and ultimately benefit pharmacotherapy for AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia that places enormous social, economic and medical burdens to our society. The research proposed in this application will validate and provide novel bivalent multifunctional A¿ oligomerization inhibitors as a strategically distinct intervention for AD patients, therefore it is relevant to public health.

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，是痴呆的主要原因。新出现的证据已经认识到淀粉样肽（A <$Os）的小的可溶性寡聚体是AD认知障碍的主要毒性物质。此外，越来越多的证据表明，氧化应激、生物金属稳态失调和神经炎症也可能有助于AD的病理学。已经开发了许多针对这些风险因素的小分子，并在临床前和临床试验中进行了测试，然而，它们中没有一个被FDA批准为AD修饰剂。这可能表明，一种替代的和有前途的策略是使用多功能配体来同时解决这些风险因素。此外，越来越多的证据强调了细胞膜/脂筏（CM/LR）在AD病理学中的重要作用，并且CM/LR与AD中所有已确定的危险因素相关。这表明，这种关系可以利用治疗开发战略不同的多功能药物，将这个因素纳入分子设计。该提案的总体果阿是验证和开发更有效的二价多功能A？寡聚化抑制剂（BMAOI），其包含具有内在抗氧化剂/金属螯合功能的多功能A？O-抑制剂和CM/LR锚定部分，作为进一步临床前研究的先导化合物。本申请的中心假设是，这些BMAOI将多功能Ao抑制剂部分锚定在CM/LR内部或附近，其中发生Ao寡聚化、Ab/生物金属相互作用和氧化应激，以增加其局部浓度和可及性，从而提高其效率。我们实验室的初步研究已经达到了BMAOIs策略的概念验证，并鉴定出两种有前途的先导化合物以供进一步优化。提出了三个具体目标来实现我们在本申请中的目标。目标一：以新发现的先导化合物为基础，设计合成一系列BMAOIs，对间隔区、CM/LR锚定结构域和A <$O-抑制剂结构域进行修饰优化。在目标2中，将在各种体外测定中评价所设计的BMAOI，包括与人神经母细胞瘤MC 65细胞中的保护活性相关的A？O形成的抑制以及对分化的SH-SY 5 Y和小鼠原代神经元的神经保护作用。还将在MC 65细胞和小鼠原代神经元中研究BMAOI与CM/LR的共定位。此外，还将测试所选BMAOI的抗氧化和金属络合性能。在目的3中，将评价通过目的2的选择标准的有效BMAOI对转基因TgCRND 8小鼠中的认知和A病理学的影响。拟议的研究是创新的，因为我们寻求一类新的BMAOIs靶向A？O，氧化应激，A？/生物金属相互作用和CM/LR作为新的药理学工具和潜在的AD修饰剂。这项研究的结果将是一种新的，经过验证的，BMAOIs策略，并最终受益于AD的药物治疗。 公共卫生关系：阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，是痴呆的主要原因，给我们的社会带来巨大的社会、经济和医疗负担。本申请中提出的研究将验证并提供新的二价多功能A？寡聚化抑制剂，作为一种战略性的独特干预措施， AD患者，因此它与公共卫生有关。