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“将基础科学发现转化为新的更好的治疗方法”的主题。该项目的目标是开发第一种选择性腺苷单磷酸脱氨酶- 2 （AMPD2）抑制剂，我们相信这将为治疗代谢综合征疾病提供一种重要的新方法。AMPD2是肝脏中主要的AMP异构体，并驱动AMP与一磷酸肌苷（IMP）和尿酸等下游产物的反应。我们的初步数据表明，AMPD2是将哺乳动物从脂肪利用转变为脂肪积累的关键酶，该途径的激活导致AMP激酶的抑制，而AMP激酶是指导脂肪利用和减少脂肪合成的关键酶。我们有间接证据表明，冬眠动物在进入冬眠状态时，amppd通路被下调，从而使它们能够激活AMP激酶并启动脂肪降解，作为利用储存能量的一种手段。相比之下，人类似乎“锁定”了脂肪的积累，这有两个机制：第一，进化导致人类尿酸酶突变，导致尿酸水平升高，我们发现尿酸水平进一步上调AMPD2；第二，因为人类饮食中添加糖中明显存在的果糖摄入，在提供底物的同时也刺激了AMPD2。抑制AMPD2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。在该提案中，我们将完成概念验证（Specific Aim 1）并开发首个针对驱动该过程的AMPD关键异构体（AMPD2）的新型药物（Specific Aim 2）。目的1将评估AMPD2在诱导代谢综合征中的作用。这将包括在正常条件下和高果糖或高脂肪饮食管理下的细胞培养研究（使用siRNA或产生阻断AMPD2活性的药物）和动物研究（通过创建转基因和敲除AMPD2小鼠）。我们还将评估Aim 2产生的AMPD2抑制剂的作用，因为它与细胞培养和动物模型中的功效、特异性和毒性有关。目标2将侧重于药物发现和开发，并将使用三种方法；a)分子建模辅助设计和优化选择性AMPD2抑制剂，该抑制剂基于已知但非选择性抑制剂coformycin的咪唑二氮环的修饰；b)在存在或不存在抑制剂的情况下，基于人类AMPD2的第一个晶体结构的分子建模（将由科罗拉多大学x射线核心设施获得）；c)通过高通量筛选AMPD2的新型原型选择性抑制剂。通过将Johnson博士基础科学实验室的专业知识与阿米达鲁斯经验丰富的药物设计团队相结合，我们预计将开发出第一个AMPD2抑制剂，该抑制剂将在3年期限结束时准备好进行I期试验。