Novel Modulators of LDL Metabolism

低密度脂蛋白代谢的新型调节剂

基本信息

批准号：
8646627
负责人：
Nabil A Elshourbagy
金额：
$ 50万
依托单位：
SHIFA BIOMEDICAL CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646627
关键词：
Accounting Animal Feed Animal Model Animals Applications Grants Binding Binding Sites Biological Biological Assay Blood Cardiovascular Diseases Catalytic Domain Cause of Death Cells Cessation of life Cholesterol Cholesterol Homeostasis Complex Computer Simulation Computers Data Set Databases Degradation Pathway Development Diet Docking Drug Targeting Education Enzyme-Linked Immunosorbent Assay Enzymes Epidermal Growth Factor Exhibits Familial Hypercholesterolemia Fatty acid glycerol esters Funding Future Goals Heart Diseases In Situ Individual LDL Cholesterol Lipoproteins Label Lead Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Metabolism Methods Modeling Mus Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Population Procedures Process Protein Precursors Recombinants Risk Factors Small Business Innovation Research Grant Structure Structure-Activity Relationship Subcutaneous Injections Subtilisin Like Proprotein Convertases Testing United States National Institutes of Health Up-Regulation Visual Woman Work analog atorvastatin base dalton design drug market efficacy testing feeding high risk hypercholesterolemia in vivo inhibitor/antagonist iterative design kexin meetings men mouse model novel phase 1 study potency testing premature prevent programs protein protein interaction public health relevance receptor receptor binding screening secretion process therapeutic target uptake virtual

项目摘要

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing between the prodomain and catalytic domain. This processing is required for PCSK9 to be secreted and to undertake its biological activity. The secreted enzyme is known to bind to the epidermal growth factor- like repeat A (EGF-A) domain of the LDLR. Our goal is to identify compounds that interfere with PCSK9 and the LDLR binding and its ability to participate in the degradation of the LDL receptor. To achieve our goal, we have integrated virtual (computer) screening methods and cell based assays and identified screening hits. Daily administration of one of these compounds to animals that are fed high fat/high cholesterol diet showed significant reduction in cholesterol level. As part of Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of the selected compounds to prevent the LDL receptor degradation, and therefore, decrease the LDL-C level using in vivo studies.

描述（由申请人提供）：心脏病是美国男性和女性死亡的主要原因，占年度死亡总数的近 40%。高胆固醇水平是众所周知的心脏病危险因素。尽管许多市售药物可以降低血液胆固醇，其中他汀类药物是主要药物，但服用这些药物的患者中只有 38% 达到了国家胆固醇教育计划 (NCEP) 设定的低密度脂蛋白胆固醇目标。此外，胆固醇水平显着升高的纯合子家族性高胆固醇血症患者对目前的药物治疗反应不佳，并且过早患心血管疾病的风险非常高。这些和其他患者将从高胆固醇血症的积极治疗中显着受益。这项工作的长期目标是开发降低胆固醇的新药。我们的治疗靶点是蛋白酶原蛋白转化酶枯草杆菌蛋白酶样 9 型 (PCSK9)。 PCSK9 控制肝脏中 LDL 受体 (LDLR) 的降解，从而有助于胆固醇稳态。 PCSK9 作为前体蛋白合成，在前结构域和催化结构域之间进行加工。 PCSK9 的分泌和发挥其生物活性需要这种处理。已知分泌的酶与 LDLR 的表皮生长因子样重复 A (EGF-A) 结构域结合。我们的目标是鉴定干扰 PCSK9 和 LDLR 结合及其参与 LDL 受体降解能力的化合物。为了实现我们的目标，我们集成了虚拟（计算机）筛选方法和基于细胞的测定，并确定了筛选结果。每天给喂食高脂肪/高胆固醇饮食的动物施用其中一种化合物，显示胆固醇水平显着降低。作为 II 期提案的一部分，我们计划扩大和优化我们的命中，并确认所选化合物防止 LDL 受体降解的能力，从而通过体内研究降低 LDL-C 水平。