Inhibition of hepatic (V)LDL production by a novel antagonist of carboxyl esterase 1

新型羧基酯酶拮抗剂 1 抑制肝脏 (V)LDL 的产生

基本信息

批准号：
10681848
负责人：
STEPHEN A DUNCAN
金额：
$ 54.71万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681848
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Affinity Alleles Binding Binding Proteins Biochemical Biological Assay Carboxylesterase 1 Cardiovascular Diseases Cells Cessation of life Characteristics Chemical Structure Cholesterol Collection Complement Coronary Arteriosclerosis Crystallography Data Enzyme Inhibition Enzymes Equilibrium Evaluation Familial Hypercholesterolemia Family Fatty Liver Formulation General Population Goals Healthcare Hepatic Hepatocyte High Density Lipoproteins Human Investigational New Drug Application LDL Cholesterol Lipoproteins Lead Left Libraries Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mass Spectrum Analysis Measures Mediating Metabolism Molecular Mus Mutation Oxidoreductase Patients Pharmaceutical Preparations Physiology Production Property Proteins Resistance Risk Role Safety Series Serum South Carolina Specificity Structure-Activity Relationship Sulfhydryl Compounds Triazines Triglycerides Variant Very low density lipoprotein Very low density lipoprotein cholesterol X-Ray Crystallography antagonist candidate identification drug discovery efficacy evaluation esterase high resolution imaging humanized mouse hypercholesterolemia induced pluripotent stem cell inhibitor liver injury loss of function mutation mouse model novel particle preclinical development prevent side effect small molecule success

项目摘要

Project Summary We used a human iPSC-derived hepatocyte platform to identify a family of structurally related small molecules that can reduce the production of APOB by the liver. These small molecules are highly effective, do not cause abnormal lipid accumulation, and have a chemical structure that is distinct from any known cholesterol lowering drug. Such compounds have the potential to treat hypercholesterolemia and steatosis. In the current application we propose to define the molecular mechanisms through which the compounds act. In preliminary data we show that the compounds inhibit human carboxylesterase 1 (CES1). In the three proposed aims we will i) identify the binding characteristics of the compounds to CES1 and define their specificity using crystallography and biochemical assays, ii) use iPSC-hepatocytes to definitively establish the role of CES1 in mediating (V)LDL-cholesterol production by the compounds, and iii) determine the efficacy of the compounds in lowering cholesterol and steatosis humanized mouse models.

项目概要我们使用人类 iPSC 衍生的肝细胞平台来鉴定一个结构相关的家族可以减少肝脏产生 APOB 的小分子。这些小分子高效，不会引起异常脂质堆积，并且具有化学结构这与任何已知的降胆固醇药物不同。此类化合物有潜力治疗高胆固醇血症和脂肪变性。在当前的应用程序中，我们建议定义化合物发挥作用的分子机制。在初步数据中我们表明化合物抑制人羧酸酯酶 1 (CES1)。在三个拟议目标中，我们将 i) 确定化合物与 CES1 的结合特征并使用以下方法定义其特异性晶体学和生化测定，ii) 使用 iPSC 肝细胞明确建立 CES1 在介导化合物产生 (V)LDL-胆固醇中的作用，以及 iii) 确定这些化合物在降低胆固醇和脂肪变性人源化小鼠模型中的功效。