Targeting the orphan nuclear receptor LRH-1 with small molecules

用小分子靶向孤儿核受体 LRH-1

基本信息

批准号：
9403854
负责人：
John Winter Calvert
金额：
$ 49万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403854
关键词：
Address Adipose tissue Agonist American Animals Antidiabetic Drugs Atherosclerosis Binding Biological Biological Assay Biology Cardiovascular Diseases Cellular Assay Cessation of life Characteristics Chemicals Clinical Collaborations Comorbidity Crystallization Deuterium Development Diabetes Mellitus Disease Drug Kinetics Epidemic Fatty Liver Fatty acid glycerol esters Genes Glucose Goals Health High Fat Diet Homeostasis Hydrogen In Vitro Insulin Insulin Resistance Knockout Mice Knowledge Lead Libraries Ligand Binding Ligands Link Lipids Liver Liver diseases Mammals Mass Spectrum Analysis Measures Metabolic Metabolic Control Metabolic Diseases Metabolic Pathway Molecular Molecular Conformation Mus Mutagenesis Myocardial Infarction NR5A2 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Orphan Receptor Obese Mice Obesity Overweight Peptides Phospholipids Plant Roots Proteins Receptor Activation Recruitment Activity Research Risk Rodent Role Series Stroke Structure Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Agents Tissues Transactivation Transcript United States Work X-Ray Crystallography analog base design detection of nutrient diabetic experimental study glucose metabolism glucose tolerance improved in vivo innovation insight insulin sensitivity lipid metabolism lipophilicity liver function mouse model new therapeutic target non-alcoholic fatty liver novel nutrition preclinical study preference prevent receptor reverse cholesterol transport scaffold small molecule tool yeast two hybrid system

项目摘要

Obesity is a growing epidemic in the United States, leading to increases in cases of nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and type 2 diabetes. A common characteristic of these diseases is aberrant lipid and glucose metabolism. This proposal centers on the nuclear hormone receptor, Liver Receptor Homolog 1 (LRH-1), which acts as an important regulator of lipid metabolism, reverse cholesterol transport, glucose sensing, and homeostasis. As such, LRH-1 represents a novel therapeutic target for metabolic diseases. LRH-1 binds to phospholipids (PLs), but until recently, the role of PLs in receptor activation was unclear. Recent studies identified dilauroylphosphatidylcholine (DLPC) as a specific LRH-1 agonist with potent anti-diabetic effects. Despite this untapped therapeutic potential, mechanisms through which LRH-1 is regulated by ligands remain poorly understood. The discovery that LRH-1 is regulated by PL ligands reveals an exciting potential to tune LRH-1 activity for the treatment of metabolic diseases. However, PLs (such as DLPC) are labile and not suitable for clinical use, necessitating the development of small molecule agonists. This has proved challenging thus far, since very few small molecules are capable of displacing endogenous lipids from the large, lipophilic binding pocket. Recent preliminary studies in our lab have characterized a potent class of small molecules that are capable of this feat. Our crystal structures of LRH-1 bound to a set of these agonists have uncovered novel mechanisms of receptor activation and have provided insights into strategies to improve agonist activity. The overall goal of this proposal is to develop improved small molecule modulators using a structure-based, rational design approach. X-ray crystallography combined with hydrogen deuterium exchange mass spectrometry, cellular assays, and animal studies will be used to address this goal in a series of three Aims. Aim 1. Design and synthesize potent, effective, and selective LRH-1 modulators Aim 2. Determine the molecular basis of allosteric modulation of LRH-1 by RJW100 analogues Aim 3. Evaluate the efficacy of LRH-1 modulators as anti-diabetic agents in obesity.

肥胖在美国日益流行，导致非酒精性脂肪肝病 (NAFLD)、心血管疾病和 2 型糖尿病病例增加。这些疾病的共同特征是脂质和葡萄糖代谢异常。该提案以核激素受体、肝受体同源物 1 (LRH-1) 为中心，它是脂质代谢、逆转胆固醇转运、葡萄糖感应和体内平衡的重要调节剂。因此，LRH-1代表了代谢疾病的新治疗靶点。 LRH-1 与磷脂 (PL) 结合，但直到最近，PLs 在受体激活中的作用尚不清楚。最近的研究发现二月桂酰磷脂酰胆碱 (DLPC) 是一种特异性 LRH-1 激动剂，具有有效的抗糖尿病作用。尽管这种治疗潜力尚未开发，但配体调节 LRH-1 的机制仍知之甚少。 LRH-1 受 PL 配体调节的发现揭示了调节 LRH-1 活性以治疗代谢疾病的令人兴奋的潜力。然而，PL（例如 DLPC）不稳定，不适合临床使用，因此需要开发小分子激动剂。迄今为止，这已被证明具有挑战性，因为很少有小分子能够从大的亲脂性结合袋中置换内源脂质。我们实验室最近的初步研究已经确定了一类能够实现这一壮举的有效小分子。我们的 LRH-1 晶体结构与一组激动剂结合，揭示了受体激活的新机制，并为提高激动剂活性的策略提供了见解。该提案的总体目标是使用基于结构的合理设计方法开发改进的小分子调节剂。 X 射线晶体学与氢氘交换质谱、细胞分析和动物研究相结合，将用于在一系列三个目标中实现这一目标。目标 1. 设计和合成强效、有效和选择性的 LRH-1 调节剂目标 2. 确定 RJW100 类似物对 LRH-1 变构调节的分子基础目标 3. 评估 LRH-1 调节剂作为抗糖尿病药物的功效肥胖。