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Structure-Based Search for Novel Antihypercholestrolemic Agent

基于结构的新型抗高胆固醇药物的搜索

基本信息

批准号：
8066009
负责人：
Sherin S Abdel-Meguid
金额：
$ 65.53万
依托单位：
SHIFA BIOMEDICAL CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-04 至 2012-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066009
关键词：
Accounting Address Adverse effects Animal Model Biological Biological Assay Blood Cardiovascular Diseases Cardiovascular system Catalytic Domain Cause of Death Cell physiology Cells Cessation of life Cholesterol Cholesterol Homeostasis Clinical Data Code Computer Simulation Computers Coronary Arteriosclerosis Data Databases Degradation Pathway Docking Education Enzyme Precursors Event Exhibits Familial Hypercholesterolemia Future Genes Genetic Goals Heart Diseases In Situ Individual Intervention LDL Cholesterol Lipoproteins Lead Length Link Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Methods Mus Mutation Nonsense Mutation Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Plasma Population Procedures Process Progress Reports Protein Precursors Recombinants Regulation Research Personnel Risk Risk Factors Screening procedure Single Nucleotide Polymorphism Specificity Structure Structure-Activity Relationship Subtilisin Like Proprotein Convertases Testing Woman Work analog base chemical synthesis drug market efficacy testing gain of function high risk hypercholesterolemia in vivo inhibitor/antagonist iterative design kexin lipid disorder loss of function loss of function mutation meetings men mortality novel potency testing premature prevent programs public health relevance 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. Our goal is to identify compounds that prevent the processing of PCSK9, thus prevent its secretion and its ability to participate in the degradation of the LDL receptor. To achieve our Phase I goal, we have integrated virtual (computer) screening methods with cell-based assays and consequently identified five screening hits. As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to stabilize the LDLR and decrease the LDL-C level using in situ and in vivo studies. 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，占所有年度死亡人数的近40%。高胆固醇水平是众所周知的心脏病危险因素。虽然可以使用许多上市药物降低血液胆固醇，其中他汀类药物是主要药物，但只有38%的服用这些药物的患者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，胆固醇水平显著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，并且早发心血管疾病的风险非常高。这些患者和其他患者将从高胆固醇血症的积极治疗中显著受益。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前蛋白转化酶枯草杆菌蛋白酶样kexin 9型（PCSK 9）。PCSK 9控制肝脏中LDL受体（LDLR）的降解，从而有助于胆固醇稳态。PCSK 9作为前体蛋白合成，其在前结构域和催化结构域之间进行加工。PCSK 9的分泌和发挥其生物活性需要这种加工。我们的目标是鉴定阻止PCSK 9加工的化合物，从而阻止其分泌及其参与LDL受体降解的能力。为了实现我们的第一阶段目标，我们将虚拟（计算机）筛选方法与基于细胞的测定相结合，从而确定了五个筛选命中。作为该II期提案的一部分，我们计划扩大和优化我们的命中，并使用原位和体内研究确认所选化合物稳定LDLR和降低LDL-C水平的能力。公共卫生相关性：心脏病是美国男性和女性的主要死亡原因。高胆固醇水平是众所周知的心脏病风险因素。虽然血液胆固醇可以使用一些上市的药物降低，但这些药物并不能治疗一部分胆固醇非常高的人群。我们的目标是开发新的降胆固醇药物，对所有胆固醇水平高的人都有影响，包括胆固醇水平非常高的人群。