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

基本信息

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
项目类别：
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&apos -adenylic acid 5&apos -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

项目摘要

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单磷酸腺苷脱氨酶-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 是存在于肝脏中的主要 AMP 亚型，驱动 AMP 与 IMP（肌苷单磷酸）和下游产物（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利用转变为脂肪积累的关键酶，并且该途径的激活会导致 AMP 激酶的抑制，AMP 激酶是指导脂肪利用和脂肪合成减少的关键酶。我们有间接证据表明，冬眠动物进入麻木状态时，AMPD 通路会被下调，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，人类似乎由于两种机制而“锁定”了脂肪堆积：首先，进化提供了人类尿酸酶突变，导致高尿酸，我们发现尿酸进一步上调 AMPD2，其次，因为人类饮食中添加糖中存在大量果糖，这也会刺激 AMPD2 并提供底物。 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，我们将完成概念验证（具体目标 1），并开发第一种新型药物，该药物将针对推动这一过程的 AMPD 关键异构体 (AMPD2)（具体目标 2）。目标 1 将评估 AMPD2 在诱导代谢综合征中的作用。这将包括正常条件下和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 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 生成的 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 将重点关注药物发现和开发，并将使用三种方法； a) 基于考福霉素（一种已知但非选择性抑制剂）的咪唑并二氮杂环的修饰，分子建模辅助设计和优化选择性 AMPD2 抑制剂； 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（通过科罗拉多大学 X 射线核心设施获得）进行分子建模； c) 通过高通量筛选 AMPD2 的新型选择性抑制剂原型。通过将 Johnson 博士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个 AMPD2 抑制剂，并将在 3 年期结束时为 I 期试验做好准备。公共卫生相关性：本申请的主题是确定肥胖和代谢综合征病因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单磷酸脱氨酶 2 (AMPD2) 在驱动导致脂肪积累和胰岛素抵抗的关键过程中的作用，在本应用中，我们提出研究开发第一个 AMPD2 抑制剂，我们预测这将提供一个重大的新途径。预防和治疗肥胖、高血压、代谢综合征和糖尿病的方法。