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：
7822161
负责人：
Nabil A Elshourbagy
金额：
$ 1.75万
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：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822161
关键词：
Accounting Address Adverse effects Area Binding Biochemical Biological Biological Assay Blood Cardiovascular Diseases Cardiovascular system Catalytic Domain Cause of Death Cell surface Cells Cessation of life Characteristics Cholesterol Cholesterol Homeostasis Clinical Data Code Complex Computer Simulation Computers Coronary Arteriosclerosis Data Databases Degradation Pathway Development Docking Drug Compounding Education Endoplasmic Reticulum Ensure Enzyme Precursors Enzymes Epidermal Growth Factor Event Familial Hypercholesterolemia Foundations Genes Genetic Goals Heart Diseases Individual Intervention Intestinal Absorption LDL Cholesterol Lipoproteins Lead Link Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolism Methods Molecular Morbidity - disease rate Mus Mutation Nonsense Mutation Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacotherapy Phase Plasma Population Process Property Proprotein Convertases Proteins Regulation Resolution Risk Risk Factors Screening procedure Sequence Analysis Serine Protease Single Nucleotide Polymorphism Site Structure Subtilisin Like Proprotein Convertases Subtilisins Surface Testing Woman Work Zinc Compounds base cost effective drug market experience extracellular gain of function high risk hypercholesterolemia in vitro Assay kexin lipid disorder loss of function loss of function mutation meetings men mortality novel premature prevent programs public health relevance therapeutic target three dimensional structure trafficking virtual

Accounting Address Adverse effects Area Binding Biochemical Biological Biological Assay Blood Cardiovascular Diseases Cardiovascular system Catalytic Domain Cause of Death Cell surface Cells Cessation of life Characteristics Cholesterol Cholesterol Homeostasis Clinical Data Code Complex Computer Simulation Computers Coronary Arteriosclerosis Data Databases Degradation Pathway Development Docking Drug Compounding Education Endoplasmic Reticulum Ensure Enzyme Precursors Enzymes Epidermal Growth Factor Event Familial Hypercholesterolemia Foundations Genes Genetic Goals Heart Diseases Individual Intervention Intestinal Absorption LDL Cholesterol Lipoproteins Lead Link Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolism Methods Molecular Morbidity - disease rate Mus Mutation Nonsense Mutation Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacotherapy Phase Plasma Population Process Property Proprotein Convertases Proteins Regulation Resolution Risk Risk Factors Screening procedure Sequence Analysis Serine Protease Single Nucleotide Polymorphism Site Structure Subtilisin Like Proprotein Convertases Subtilisins Surface Testing Woman Work Zinc Compounds base cost effective drug market experience extracellular gain of function high risk hypercholesterolemia in vitro Assay kexin lipid disorder loss of function loss of function mutation meetings men mortality novel premature prevent programs public health relevance therapeutic target three dimensional structure trafficking virtual

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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 a well-known risk factor 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 achieve 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 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 interface between the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) and the low density lipoprotein receptor (LDLR), where we propose to identify and develop compounds that prevent PCSK9 from binding to the LDLR. PCSK9 regulates the degradation of the LDLR in the liver by binding to LDLR on the cell surface, and thereby contributes to cholesterol homeostasis. PCSK9 is made as a zymogen that requires autocatalytic processing for proper secretion; the secreted enzyme is known to bind to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Our attempts to interfere with the interface between PCSK9 and the LDLR will be facilitated by the availability of the crystal structure of the PCSK9/LDLR-EGF-A complex. To achieve our goal, we will integrate virtual (computer) screening methods and in vitro assays to identify lead compounds that can potentially be optimized to produce cholesterol lowering drugs. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen million of compounds to identify a small set to be purchased and tested in a biological, biophysical or biochemical assay. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind to PCSK9 and block its binding to the LDLR. 2. Use in vitro assays to confirm the ability of the selected compounds to bind to PCSK9 and prevent its binding to the LDLR. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a segment of the population with very high cholesterol. Our goal is to develop new cholesterol lowering drugs that have an effect on all individuals with high cholesterol levels, including that segment of the population having very high cholesterol levels.

描述（由申请人提供）：心脏病是美国男性和女性的主要死亡原因，占所有年死亡的近40％。高胆固醇水平是心脏病的众所周知的危险因素。尽管可以使用多种销售药物降低血液胆固醇，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％实现了由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，纯合性家族高胆固醇血症的患者对当前药物治疗的反应较差，并且患心血管早熟的风险很高。这些和其他患者将受益于高胆固醇血症的积极治疗。这项工作的长期目标是开发降低胆固醇的新药物。我们的治疗靶标是蛋白酶前蛋白转化酶枯草蛋白样的KEXIN类型9（PCSK9）与低密度脂蛋白受体（LDLR）之间的接口，我们建议在其中识别和开发防止PCSK9与LDLR结合的化合物。 PCSK9通过与细胞表面上的LDLR结合，从而调节LDLR在肝脏中的降解，从而导致胆固醇稳态。 PCSK9是一种Zymogen，需要进行自催化处理以进行适当的分泌。已知分泌的酶与LDLR的表皮生长因子样重复A（EGF-A）结构结合。我们试图通过PCSK9/LDLR-EGF-A复合物的晶体结构的可用性来促进PCSK9和LDLR之间的接口。为了实现我们的目标，我们将整合虚拟（计算机）筛选方法和体外测定法，以识别有可能优化以生产胆固醇降低药物的铅化合物。虚拟筛选需要靶蛋白的原子分辨率3D结构的可用性，它为筛选百万种化合物的成本有效方法提供了识别要在生物，生物物理或生化测定中购买和测试的小型集合。这项工作的具体目的是：1。使用虚拟筛选方法识别与PCSK9结合并阻止其与LDLR结合的化合物。 2。使用体外测定法确认所选化合物与PCSK9结合并防止其与LDLR结合的能力。公共卫生相关性：心脏病是美国男女死亡的主要原因。高胆固醇水平是心脏病的众所周知的危险因素。尽管可以使用多种销售药物来降低血液胆固醇，但这些药物并不能以非常高的胆固醇治疗一部分人群。我们的目标是开发新的胆固醇降低药物，这些药物对所有胆固醇水平较高的人都有影响，包括胆固醇水平很高的人群。