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Pre-clinical studies to explore the therapeutic potential of insulin-degrading enzyme inhibitors

探索胰岛素降解酶抑制剂治疗潜力的临床前研究

基本信息

批准号：
9272160
负责人：
Alan Saghatelian
金额：
$ 33.15万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272160
关键词：
Agonist Amyloid beta-Protein Animal Model Animals Binding Blood Glucose Brain Chronic Clinical Computer Simulation DNA Data Development Diabetes Mellitus Diabetic mouse Drug Combinations Drug Industry Drug Targeting Eating Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Epidemic FDA approved Fasting Gastric Emptying Genes Glucagon Glycosylated hemoglobin A Goals Health Hormones Human Insulin Insulin Receptor Insulin Resistance Insulinase Investigation Knockout Mice Lead Libraries Liver Metalloproteases Metformin Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Pancreatic Hormones Paper Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Physiology Pramlintide Renal function Reporting Safety Signal Pathway Site Staging Structure Structure-Activity Relationship Surface Synthesis Chemistry Testing Therapeutic Validation Weight Work amylin receptor analog base design diabetic drug development drug discovery effective therapy enzyme substrate feeding genome wide association study glucose metabolism glucose production glucose tolerance impaired glucose tolerance improved in vivo insulin signaling interest islet amyloid polypeptide liver function neurolysin new therapeutic target novel oral glucose tolerance preclinical study prevent research study screening small molecule structural biology thimet oligopeptidase

项目摘要

DESCRIPTION (provided by applicant): Diabetes is a growing epidemic, and the increasing number of type 2 diabetics highlights the need for novel, mechanistically distinct, therapeutics. In this application, the potential of insulin-degrading enzyme (IDE) inhibitors as diabetes drugs will be explored. Preceding work led to the discovery of 6bK, a small-molecule macrocycle IDE inhibitor. 6bK is a remarkably selective IDE inhibitor with greater than 1000-fold selectivity over related metalloproteases. Structural studies determined that this selectivity comes from 6bK binding to a unique site on the IDE surface (referred to as the "IDE-selectivity pocket"). Though other IDE inhibitors have been reported, 6bK is the only IDE inhibitor that is active in vivo. Usin 6bK, the physiological impact of IDE inhibition in mouse models of diabetes (HFD-fed mice) was tested and 6bK-treated mice had higher insulin levels and improved oral glucose tolerance compared to vehicle-treated animals. Furthermore, these experiments revealed that the pancreatic hormones amylin and glucagon are also endogenous IDE substrates. Pramlintide, an amylin analog and amylin receptor agonist, is an FDA-approved drug that slows gastric emptying to control postprandial blood glucose levels. This information was used to demonstrate that 6bK slows gastric emptying by raising endogenous amylin levels, providing a second signaling pathway that 6bK uses to lower blood glucose levels. IDE inhibitors are worth further investigation because they represent a mechanistically distinct class of potential diabetes drugs; the only compounds that raise insulin and amylin levels by impairing the degradation of these hormones. Medicinal chemistry, structural biology, and physiology will be used to determine the clinical potential of IDE inhibitors. First, 6bK will be used to determine whether chronic IDE inhibition is a safe and effective treatment of diabetes in animal models (Aim 1). Next, novel IDE inhibitors that were designed using structure-activity-relationships, structural biology, and computation will be generated and tested (Aim 2). Finally, IDE inhibitors will be used in combination with approved diabetic drugs to identify synergistic effects on lowering blood glucose levels (Aim 3). These experiments might reveal combinations of compounds, including IDE drugs, that will be most useful clinically. Together these studies should provide the clearest picture of the clinical potential of IDE inhibitors, and reveal compounds that can serve as useful lead compounds for drug development.