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: 8517538
• 负责人: Shijun Zhang
• 金额: $ 30.41万
• 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/8517538
• 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.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病，是痴呆症的主要原因。新兴的证据已经识别出淀粉样蛋白肽（A肽）的小固体低聚物是AD中认知障碍的主要有毒物种。此外，有证据表明，氧化物胁迫，生物多膜瘤和神经炎症也可能有助于AD的病理。在临床前和临床试验中已经开发并测试了许多针对这些危险因素的小分子，但是，没有一个被FDA批准为AD修饰剂。这可能表明，另一种和承诺的策略之一是使用多功能配体简单地应对这些危险因素。此外，已经实施了细胞膜/脂质筏（CM/LR）在AD和CM/LR病理学中的重要作用，以与AD中的所有确定危险因素相关联。这表明可以热探索这种关系，以通过将该因子纳入分子设计中来开发战略性不同的多功能药物。该提案的总体果阿是验证和开发更多潜在的二价多功能A寡聚抑制剂（BMAOIS），该抑制剂（BMAOIS）包含具有固有抗氧化剂/金属螯合功能的多功能A抑制剂，以及CM/LR锚定成分作为CM/LR锚固型，作为铅的铅化合物，以进一步进行综合研究。该应用的中心假设是，这些BMAOI将锚定内部或在CM/LR附近的多功能A抑制剂部分，其中A寡聚，AB/Biometal相互作用，AB/Biometal相互作用以及氧化应激会增加其局部浓度和可及性，从而提高了其效率。我们实验室的初步研究已经达到了BMAOIS策略的概念验证，并导致了两种有希望的铅化合物以进一步优化。提出了三个具体目标来实现我们在本应用中的目标。在AIM 1中，将根据新确定的铅化合物设计和合成一系列的BMAOIS，以修改和优化间隔域，CM/LR锚固域和A O抑制剂域。在AIM 2中，设计的BMAOI将在各种体外评估中进行评估，包括抑制A形成与人类神经母细胞瘤MC65细胞中的保护活性以及对分化的SH-SY5Y和小鼠原发性神经元的神经保护作用。 BMAOI与CM/LR的共定位也将在MC65细胞和小鼠原发性神经元中进行研究。另外，将测试选定BMAOI的抗氧化剂和金属络合性能。在AIM 3中，将评估通过AIM 2的选择标准的潜在BMAOI对转基因TGCRND8小鼠的认知和病理影响的影响。拟议的研究具有创新性，因为我们寻求针对A OS，氧化应激，A /生物识别相互作用以及CM /LR的新的BMAOIS作为新型药理工具和潜在的AD修饰剂。这项研究的结果将是一种新颖，经过验证的BMAOIS策略，并最终使AD药物疗法受益。