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”。该项目的目的是开发第一个选择性腺苷单磷酸脱氨酶-2（AMPD2）抑制剂，我们认为这将为代谢综合征疾病提供一种重要的新方法。 AMPD2是存在于肝脏中的主要AMP同工型，并驱动AMP对IMP（肌苷单磷酸盐）和下游产物（例如尿酸）的反应。我们的初步数据表明，AMPD2是将哺乳动物从脂肪使用转变为脂肪积累的关键酶，并且该途径的激活导致AMP激酶的抑制作用，AMP激酶是一种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途径在进入Torpor时被冬眠的动物下调，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手段。相比之下，由于两种机制，人类似乎被“锁定”是脂肪积累的：首先，进化为尿酸酶提供了一种导致高尿酸的人类突变，我们发现它进一步上调了AMPD2，其次是在饮食中添加的饮食中添加的糖含量促进ampd2 and Ampd2的含糖量显着摄入，因此促进了Ampd2的含量。 AMPD2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。在此提案中，我们将完成概念证明（特定目标1），并开发新的药物中的第一类，该药物将针对推动这一过程的AMPD的关键同工型（AMPD2）（特定的AIM 2）。 AIM 1将评估AMPD2在诱导代谢综合征中的作用。这将包括细胞培养研究（使用siRNA或产生的阻断AMPD2活性的药物）和动物研究（通过在正常情况下创建转基因和敲除AMPD2小鼠）以及在施用高果糖或高脂肪饮食之后。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。 AIM 2将专注于药物发现和开发，并将使用三种方法； A）基于选择性AMPD2抑制剂的分子建模辅助设计和优化，基于辅实二氮杂霉素环（一种已知但非选择性抑制剂）的修饰； b）基于在存在或不存在抑制剂的情况下，基于人AMPD2的第一个晶体结构（可以用科罗拉多大学X射线核心设施获得）； c）通过高吞吐量筛选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Amidaerus的经验丰富的药物设计团队相结合，我们希望开发第一个在3年结束时进行I期试验的AMPD2抑制剂。 公共卫生相关性：确定肥胖和代谢综合征病因的新颖途径，以及潜在的新疗法，是该应用程序的主题。具体而言，我们已经确定了腺苷单磷酸脱氨酶-2（AMPD2）在驱动促进脂肪积累和胰岛素抵抗的关键过程中的作用，在此应用中，我们建议开发第一种AMPD2抑制剂，我们预测，我们预测，该方法将为预防和治疗肥胖，高含量，高含量，代理，代理，疾病和疾病，和治疗肥胖，疾病和疾病。