Novel Modulators of LDL Metabolism

描述(申请人提供)：心脏病是美国男性和女性的主要死亡原因，占每年死亡人数的近40%。高胆固醇水平是众所周知的心脏病风险因素。尽管一些上市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%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较差，并有较高的过早心血管疾病风险。这些患者和其他患者将极大地受益于积极的高胆固醇血症治疗。这项工作的长期目标是开发降低胆固醇的新药。我们的治疗目标是蛋白酶原蛋白转换酶类枯草杆菌蛋白类似kexin 9(PCSK9)和低密度脂蛋白受体(LDLR)之间的接口，在那里我们建议识别和开发阻止PCSK9与LDLR结合的化合物。PCSK9通过与细胞表面的低密度脂蛋白受体结合来调节肝脏低密度脂蛋白受体的降解，从而促进胆固醇的稳态。PCSK9是一种需要自动催化处理才能正常分泌的酶原；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。PCSK9/LDLR-EGF-A复合体的晶体结构将有助于我们干扰PCSK9和LDLR之间的界面。为了实现我们的目标，我们将整合虚拟(计算机)筛选方法和体外分析，以确定可能优化的先导化合物，以生产降胆固醇药物。虚拟筛选需要获得目标蛋白质的原子分辨率3D结构，它提供了一种成本效益高的方法来筛选数百万种化合物，以识别要购买的一小套化合物，并在生物、生物物理或生化分析中进行测试。这项工作的具体目的是：1.使用虚拟筛选方法来鉴定与PCSK9结合的化合物并阻断其与LDLR的结合。2.使用体外实验确认所选化合物与PCSK9结合的能力，并阻止其与LDLR结合。与公共健康相关：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。虽然使用一些市面上销售的药物可以降低血液中的胆固醇，但这些药物并不能治疗一部分胆固醇水平非常高的人群。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个人都有效，包括胆固醇水平非常高的人群。

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.