Structure-Based Search for Novel Antihypercholestrolemic Agent

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，但在服用这些药物的患者中，只有38%的患者实现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，并有非常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。我们的治疗靶点是蛋白酶原蛋白转换酶类枯草杆菌毒素9(PCSK9)。PCSK9控制肝脏低密度脂蛋白受体(LDLR)的降解，从而促进胆固醇的动态平衡。PCSK9是作为前体蛋白合成的，在原结构域和催化域之间进行加工。这一过程是PCSK9分泌和进行生物活性所必需的。我们的目标是确定阻止PCSK9加工的化合物，从而阻止其分泌及其参与低密度脂蛋白受体降解的能力。为了实现我们的第一阶段目标，我们将虚拟(计算机)筛查方法与基于细胞的分析相结合，从而确定了五种筛查命中。作为这项第二阶段计划的一部分，我们计划扩大和优化我们的HITS，并利用现场和体内研究证实选定的化合物稳定LDLR和降低低密度脂蛋白-C水平的能力。 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 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.