Novel Modulators of LDL Metabolism

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，占每年所有死亡人数的近40%。众所周知，高胆固醇是心脏病的危险因素。虽然市面上有许多降低血胆固醇的药物，其中他汀类药物是最主要的药物，但只有38%的患者服用这些药物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，胆固醇水平明显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，并且存在过早发生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新型降胆固醇药物。我们的治疗靶点是蛋白酶蛋白转化酶枯草素样keexin 9 （PCSK9）和低密度脂蛋白受体（LDLR）之间的界面，我们建议鉴定和开发阻止PCSK9与LDLR结合的化合物。PCSK9通过与肝脏细胞表面的LDLR结合来调节肝脏内LDLR的降解，从而促进胆固醇稳态。PCSK9是一种酶原，需要自催化处理才能正常分泌；分泌的酶已知与LDLR的表皮生长因子样重复A （EGF-A）结构域结合。PCSK9/LDLR- egf - a复合物晶体结构的可用性将有助于我们干扰PCSK9和LDLR之间界面的尝试。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，以确定可能被优化以生产降胆固醇药物的先导化合物。虚拟筛选需要获得目标蛋白的原子分辨率3D结构，为筛选数百万种化合物提供了一种经济有效的方法，以确定需要购买的一小组化合物，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。使用虚拟筛选方法鉴定与PCSK9结合并阻断其与LDLR结合的化合物。2. 使用体外实验确认所选化合物与PCSK9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死亡的主要原因。众所周知，高胆固醇是心脏病的危险因素。虽然市面上的一些药物可以降低血胆固醇，但这些药物并不能治疗高胆固醇人群。我们的目标是开发新的降胆固醇药物，对所有高胆固醇人群都有效，包括那些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.