Druggable regulators of nitric oxide production as new Alzheimer's disease therap

摘要：亚硝化应激是阿尔茨海默病（AD）发病和进展的关键介质：在动物疾病模型中，亚硝化应激先于并与神经营养不良和树突状脊柱丧失、a¿/淀粉样蛋白积累和沉积、胆碱能失神经支配和记忆丧失表型相关。正常情况下，一氧化氮（NO）是一种重要的信号分子，产生它的酶一氧化氮合酶（NOS）通过亚硝基化调节ApoE及其其他蛋白质伙伴。在促炎条件下（如AD），氧化应激上调NOS，过量的NO与氧自由基结合形成反应性亚硝基化物质过氧亚硝酸盐，从而导致混杂失调和不加区分的损伤。由于NOS的直接抑制会导致全身毒性，我们的独特策略是选择性地降低炎症部位的NO活性。这将通过靶向Sigma- 1受体（S1R）来实现，因为它们仅在氧化应激条件下成为NOS活性的重要调节因子。我们的假设是，通过促进s1r介导的NOS活性降低的药物，可以降低炎症部位升高的脑NO水平。发现和概念验证阶段的路径包括：A)合成额外的新候选分子，赋予化合物适当的选择性和药物样特性，降低NO水平，促进体外亚硝化应激条件下神经元和/或胶质细胞的存活；B)通过测量中枢神经系统a /淀粉样蛋白负荷的减少、3-硝基酪氨酸水平和认知能力的改善，在AD转基因小鼠模型中评估这些导联中的1-。在我们的初步工作中已经确定了新的高亲和力S1R候选物（hit），现在我们寻求创造具有精细药物样特性的先导物，以测试我们的靶向和基于机制的治疗假设，旨在减缓AD的进展。

DESCRIPTION (provided by applicant): Druggable regulators of nitric oxide production as new Alzheimer's disease therapeutics Summary: Nitrosative stress is a critical mediator of the onset and progression of Alzheimer's disease (AD): it precedes and is associated with neuritic dystrophy and dendritic spine loss, A¿/amyloid accumulation and deposition, cholinergic denervation and a memory loss phenotype in animal models of disease. Normally, nitric oxide (NO) is an important signaling molecule and the enzyme that produces it, nitric oxide synthase (NOS), regulates ApoE and its other protein partners via nitrosylation. Under pro-inflammatory conditions (e.g. AD), oxidative stress upregulates NOS. Excess NO combines with oxygen radicals forming the reactive nitrosylating species peroxynitrite, which in turn causes promiscuous dysregulation and indiscriminate damage. Because direct inhibition of NOS results in systemic toxicity, our unique strategy is to selectively reduce NO activity at sites of inflammation. This will be achieved by targeting Sigma- 1 receptors (S1R), because they become important regulators of NOS activity only under conditions of oxidative stress. Our hypothesis is that elevated brain NO levels can be lowered at inflammatory sites by drugs that promote S1R-mediated reductions in NOS activity. The path for discovery and proof-of-concept phases includes: A) synthesis of additional novel candidate molecules to impart the appropriate selectivity and drug-like characteristics to compounds that reduce NO levels and promote neuronal and/or glial cell survival in vitro under conditions of nitrosative stress; B) evaluate 1- of these leads in a transgenic mouse model of AD by measuring reductions in CNS A¿/amyloid burden, 3-nitrotyrosine levels and improvements in cognition. Novel high affinity S1R candidates (hits) have been identified in our preliminary work and now we seek to create leads with refined drug-like properties for testing our target and mechanism- based hypothesis for therapeutics designed to slow the progression of AD. PUBLIC HEALTH RELEVANCE: The objective is to discover and develop news drugs for the treatment of Alzheimer's disease, a leading cause of morbidity and mortality in the US.