Novel Modulators of LDL Metabolism

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风险因素。尽管许多上市药物可以降低血胆固醇，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较差，并且具有早发心血管疾病的高风险。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）和低密度脂蛋白受体（LDLR）之间的界面，我们建议在此识别和开发阻止PCSK 9与LDLR结合的化合物。PCSK 9通过与细胞表面上的LDLR结合来调节肝脏中LDLR的降解，从而有助于胆固醇稳态。PCSK 9是一种酶原，需要自催化处理才能正常分泌;已知分泌的酶与LDLR的表皮生长因子样重复序列A（EGF-A）结构域结合。我们干扰PCSK 9和LDLR之间界面的尝试将通过PCSK 9/LDLR-EGF-A复合物的晶体结构的可用性来促进。为了实现我们的目标，我们将整合虚拟（计算机）筛选方法和体外试验，以确定可能优化生产降胆固醇药物的先导化合物。虚拟筛选需要靶蛋白的原子分辨率3D结构的可用性，提供了一种具有成本效益的方法来筛选数百万种化合物，以确定要购买的小集合并在生物，生物物理或生物化学测定中进行测试。本工作的具体目标是：1。使用虚拟筛选方法鉴定与PCSK 9结合并阻断其与LDLR结合的化合物。2.使用体外试验确认所选化合物与PCSK 9结合并阻止其与LDLR结合的能力。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。

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.