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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.