Development of inhibitors of AMP Deaminase Isoform 2 as a Mechanism for Treating

开发 AMP 脱氨酶异构体 2 抑制剂作为治疗机制

• 批准号: 8046591
• 负责人: Richard Joseph Johnson
• 金额: $ 227.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046591
• 关键词: 2' -adenylic acid; 5' -AMP-activated protein kinase; AMP Deaminase; Aconitate Hydratase; Adenosine Monophosphate; Adipocytes; Animal Model; Animals; Automobile Driving; Award; Basic Science; Biochemical Pathway; Body Weight decreased; Calories; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Clinical; Clinical Research; Coformycin; Colorado; Computer Simulation; Core Facility; Coupled; Data; Deaminase; Development; Diabetes Mellitus; Diet; Disease; Drug Delivery Systems; Drug Design; Enoyl-CoA Hydratase; Enzymes; Epidemic; Equilibrium; Etiology; Evolution; Exercise; Fatty Liver; Fatty acid glycerol esters; Fructose; Generations; Genetic; Goals; Hepatocyte; Hour; Human; Hypertension; Individual; Ingestion; Inosine Monophosphate; Insulin Resistance; Intake; Knock-out; Knockout Mice; Laboratories; Lead; Leptin; Liver; Mammals; Metabolic syndrome; Methods; Mitochondria; Modeling; Modification; Molecular; Molecular Models; Morbidity - disease rate; Mus; Mutation; Nature; Obesity; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Process; Protein Isoforms; Purines; Rattus; Reaction; Regulatory Pathway; Research; Review Literature; Roentgen Rays; Role; Scientist; Secondary to; Small Interfering RNA; Specificity; Squirrel; Structure; Testing; Time; Toxic effect; Transgenic Organisms; Translating; United States National Institutes of Health; Universities; Urate Oxidase; Uric Acid; Waste Products; Work; abstracting; adenylate kinase; authority; base; cost; design; drug discovery; experience; fatty acid oxidation; high throughput screening; inhibitor/antagonist; insight; interest; mitochondrial dysfunction; molecular modeling; novel; novel strategies; oxidation; prevent; prototype; purine; sugar

DESCRIPTION (provided by applicant): Our application belongs to the theme, "Translating Basic Science Discoveries into New and Better Treatments". The goal of the project is to develop the first selective adenosine monophosphate deaminase- 2 (AMPD2) inhibitor, which we believe will offer an important new method of treatment for diseases of metabolic syndrome. AMPD2 is the predominant AMP isoform that is present in liver and drives the reaction of AMP to IMP (inosine monophosphate) and downstream products such as uric acid. Our preliminary data suggests that AMPD2 is the key enzyme that switches mammals from fat utilizing to fat accumulating, and that activation of this pathway results in the inhibition of AMP kinase, a key enzyme that directs fat utilization and a reduction in fat synthesis. We have indirect evidence that the AMPD pathway is down-regulated by hibernating animals as they enter torpor, thus allowing them to activate AMP kinase and initiate fat degradation as a means to utilize stored energy. In contrast, humans appear to be "locked in" to be fat accumulating due to two mechanisms: first, evolution has provided a human mutation in uricase that results in high uric acid, which we have found further up-regulates AMPD2, and second, because of the marked intake of fructose present in added sugars of the human diet that also stimulates AMPD2 along with providing substrate. Inhibition of AMPD2 appears to be a novel mechanism for preventing and treating metabolic syndrome, obesity, diabetes and cardiovascular disease. In this proposal we will both complete a proof of concept (Specific Aim 1) and develop the first of a new class of drugs that will target the key isoform of AMPD that is driving this process (AMPD2) (Specific Aim 2). Aim 1 will evaluate the role for AMPD2 in inducing metabolic syndrome. This will consist of cell culture studies (using siRNA or drugs generated that block AMPD2 activity) and animal studies (by creating transgenic and knockout AMPD2 mice) under both normal conditions and following the administration of a high fructose or high fat diet. We will also evaluate the role of AMPD2 inhibitors generated from Aim 2 as it relates to efficacy, specificity and toxicity in cell culture and animal models. Aim 2 will focus on drug discovery and development and will use three approaches; a) molecular modeling aided design and optimization of a selective AMPD2 inhibitor based on modification of the imidazodiazepine ring of coformycin, a known but nonselective inhibitor; b) molecular modeling based on the first crystal structure of human AMPD2 ( to be obtained with the University of Colorado X-ray Core Facility) in the presence or absence of inhibitors; and, c) by high- throughput screening for novel prototype selective inhibitors of AMPD2. By combining the expertise of the basic science laboratory of Dr. Johnson with the highly experienced drug design team from Amidaerus, we expect to develop the first AMPD2 inhibitor that will be ready for Phase I trials at the end of the 3 year period. PUBLIC HEALTH RELEVANCE: Identifying novel pathways for the etiology of obesity and metabolic syndrome, and potentially new therapies, is the topic of this application. Specifically, we have identified a role for adenosine monophosphate deaminase-2 (AMPD2) in driving key processes that lead to fat accumulation and insulin resistance, and in this application we propose studies to develop the first AMPD2 inhibitor which we predict will provide a major new approach for preventing and treating obesity, hypertension, metabolic syndrome, and diabetes.

描述（由申请人提供）：我们的申请属于主题，“将基础科学发现转化为新的更好的治疗方法”。该项目的目标是开发第一个选择性腺苷酸脱氨酶-2（AMPD 2）抑制剂，我们相信这将为代谢综合征疾病提供一种重要的新治疗方法。AMPD 2是存在于肝脏中的主要AMP同种型，并驱动AMP反应为IMP（肌苷一磷酸）和下游产物（如尿酸）。我们的初步数据表明，AMPD 2是将哺乳动物从脂肪利用转变为脂肪积累的关键酶，并且该途径的激活导致AMP激酶的抑制，AMP激酶是指导脂肪利用和减少脂肪合成的关键酶。我们有间接的证据表明，AMPD途径是下调冬眠动物，因为他们进入麻木，从而使他们能够激活AMP激酶和启动脂肪降解作为一种手段，利用储存的能量。相比之下，由于两种机制，人类似乎被“锁定”为脂肪积累：第一，进化提供了尿酸酶的人类突变，导致高尿酸，我们发现这进一步上调AMPD 2，第二，由于人类饮食中添加的糖中存在的果糖的显著摄入，这也刺激AMPD 2沿着提供底物。AMPD 2的抑制似乎是预防和治疗代谢综合征、肥胖、糖尿病和心血管疾病的新机制。在这项提案中，我们将完成概念验证（具体目标1），并开发第一类新药物，这些药物将靶向驱动这一过程的AMPD关键亚型（AMPD 2）（具体目标2）。目的1探讨AMPD 2在代谢综合征中的作用。这将包括在正常条件下和给予高果糖或高脂肪饮食后的细胞培养研究（使用siRNA或产生的阻断AMPD 2活性的药物）和动物研究（通过创建转基因和敲除AMPD 2小鼠）。我们还将评估Aim 2产生的AMPD 2抑制剂的作用，因为它与细胞培养和动物模型中的疗效、特异性和毒性有关。目标2将集中于药物发现和开发，并将使用三种方法：a）分子建模辅助设计和优化选择性AMPD 2抑制剂，其基于对已知但非选择性抑制剂coformycin的咪唑二氮杂环的修饰; B）基于人AMPD 2的第一晶体结构的分子建模（由科罗拉多大学X射线核心设施获得）;和，c）通过高通量筛选AMPD 2的新原型选择性抑制剂。通过将约翰逊博士的基础科学实验室的专业知识与Amidaerus经验丰富的药物设计团队相结合，我们预计将开发出第一种AMPD 2抑制剂，并将在3年期结束时进行I期试验。 公共卫生关系：本申请的主题是确定肥胖和代谢综合征病因学的新途径以及潜在的新疗法。具体来说，我们已经确定了腺苷一磷酸脱氨酶-2（AMPD 2）在驱动导致脂肪积累和胰岛素抵抗的关键过程中的作用，在本申请中，我们提出了开发第一种AMPD 2抑制剂的研究，我们预测这将为预防和治疗肥胖症、高血压、代谢综合征和糖尿病提供一种重要的新方法。