Discovery of Natural Product Inhibitors of Fructose-1,6-bisphophatase for Obesity Management

用于肥胖管理的果糖 1,6-二磷酸酶天然产物抑制剂的发现

基本信息

批准号：
9197188
负责人：
Michael Rush
金额：
$ 2.29万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-06-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197188
关键词：
Active Sites Adult Adverse effects Affinity American Amination Amines Anti-Inflammatory Agents Anti-Obesity Agents Anti-inflammatory Arachidonate 15-Lipoxygenase Bacteria Binding Biochemical Pathway Biochemistry Biological Biological Assay Blood Glucose Botanical dietary supplements Botanicals Carbohydrates Carboxylic Acids Centers for Disease Control and Prevention (U.S.)Chemicals Chemistry Chicago Collection Complex Complex Mixtures Computer software Cyanobacterium Data Databases Development Diabetes Mellitus Diet Drug Industry Enzymes Fructose Fructose-1,6-Bisphosphatase Glucose Grant Health Care Costs Hybrids Hypoglycemic Agents Illinois Immobilization Individual Inflammation Insulin Laboratories Lead Libraries Ligands Magnetism Maintenance Marines Mass Spectrum Analysis Medical Metabolic Pathway Metabolic syndrome Metabolism Microspheres N-hydroxysulfosuccimide Native Americans Natural Products Nature Non obese Obesity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacognosy Pharmacologic Substance Plants Property Public Health Recombinants Research Resolution Resources Site Source Speed Standardization Structure Sulfonylurea Compounds Technology Testing Therapeutic Agents Training United States United States National Institutes of Health Universities Weight Woman Youth base cofactor computerized data processing cost design dietary supplements drug development experimental study fight against follow-up health economics high throughput screening inhibitor/antagonist mass spectrometer metabolomics microbial novel novel therapeutics obesity management pre-doctoral prevent public health relevance receptor scaffold screening structural biology sugar

项目摘要

DESCRIPTION (provided by applicant): Approximately one-third of Americans are obese resulting in over $1,400 extra health care costs per capita each year in the United States, which makes obesity a major public health and economics issue. Unabated high caloric diets can lead to obesity and associated medical. Anti-hyperglycemic agents such as sulfonylureas and biologicals such as insulin control free glucose levels but do not necessarily prevent obesity. There is vast potential to discover new therapeutic agents to help prevent excessive carbohydrate related obesity. Nature provides broad chemical diversity, and natural products continue to be sources of new chemical scaffolds and new classes of compounds for a wide range of therapeutic agents. The research of this predoctoral training grant will be to discover natural product inhibitors of the gluconeogenic enzyme, fructose-1,6- bisphosphatase (FBP). FBP functions as a gluconeogenic enzyme without involvement in any other biochemical or metabolic pathways; undesirable side effects that are common to less specific targets can be avoided. Although the pharmaceutical industry has validated FBP as a viable anti-obesity target, the only promising compounds weakly bind to a cofactor receptor site. Therefore, ligands to the active site of FBP and potent inhibitors of any type remain undiscovered; the diversity of natural products represents an unexplored resource for lead compounds. The primary impediment to the discovery of natural product lead compounds is that most natural products exist in complex mixtures and are not compatible with most high-throughput screening approaches. To overcome this impediment, I have been developing high-throughput mass spectrometry-based assays that are designed for identifying active compounds within complex mixtures. Specifically, my preliminary data show that microbead affinity selection screening (MMASS; invented in the laboratory of sponsor Dr. van Breemen), which uses high resolution UHPLC-MS and metabolomics-type data processing, provides the selectivity and speed required for screening complex natural product mixtures. Using the inflammation target 15-lipoxygenase (15-LOX) to establish proof of concept, I enhanced the throughput of MMASS by approximately 100-fold and then applied it to the discovery of a 15-LOX inhibitors in extracts of 15 North American prairie plants used by Native American women for their anti-inflammatory properties. These assays resulted in the identification of quercitrin as a 15-LOX inhibitor in an extract of mermaid weed. To complete my dissertation research, I will use MMASS to test botanical extracts provided by the UIC/NIH Center for Botanical Dietary Supplements, natural product libraries and extracts of microbial cultures available at UIC for potential new inhibitors of FBP. The IC50 values and mechanisms of inhibition of the hits will then be determined. There is significant need to identify new compounds that inhibit FBP and tapping the chemical diversity of natural products will provide lead compounds with perhaps unique scaffolds and novel binding mechanisms.

描述（由申请人提供）：大约三分之一的美国人患有肥胖症，导致美国每年人均额外医疗费用超过 1,400 美元，这使得肥胖成为一个主要的公共卫生和经济问题。持续的高热量饮食可能会导致肥胖。肥胖和相关医疗磺酰脲类等抗高血糖药物和胰岛素等生物制剂可控制游离血糖水平，但不一定能预防肥胖。有助于预防过量碳水化合物相关肥胖的新治疗剂大自然提供了广泛的化学多样性，天然产物仍然是各种治疗剂的新化学支架和新化合物的来源。这项博士前培训资助的研究将是。发现糖异生酶、果糖-1,6-二磷酸酶 (FBP) 的天然产物抑制剂，其作为糖异生酶发挥作用，而不涉及任何其他常见的生化或代谢途径；尽管制药行业已验证 FBP 作为可行的抗肥胖靶点，但唯一有前途的化合物与辅因子受体位点的结合较弱，因此，FBP 活性位点的配体和任何类型的有效抑制剂仍然存在。尚未发现；天然产物的多样性代表了先导化合物的未开发资源发现天然产物先导化合物的主要障碍是大多数天然产物存在于复杂的混合物中并且与大多数高通量筛选方法不兼容。为了克服这一障碍，我一直在开发基于高通量质谱的检测方法，旨在识别复杂混合物中的活性化合物。具体来说，我的初步数据显示微珠亲和选择筛选（MMASS；由赞助商 van Breemen 博士的实验室发明）。），它使用高分辨率 UHPLC-MS 和代谢组学类型的数据处理，提供使用炎症目标 15-脂氧合酶 (15-LOX) 筛选复杂天然产物混合物所需的选择性和速度。为了进行概念验证，我将 MMASS 的吞吐量提高了大约 100 倍，然后将其应用于在美洲原住民妇女使用的 15 种北美草原植物提取物中发现 15-LOX 抑制剂，这些植物具有抗炎特性。这些测定结果鉴定出美人鱼草提取物中的槲皮苷为 15-LOX 抑制剂。为了完成我的论文研究，我将使用 MMASS 测试由该公司提供的植物提取物。 UIC/NIH 植物膳食补充剂中心、UIC 提供的潜在新 FBP 抑制剂的天然产物库和微生物培养物提取物将确定 IC50 值和抑制机制。抑制 FBP 的新化合物和利用天然产物的化学多样性将为先导化合物提供可能独特的支架和新颖的结合机制。