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。已知这种分泌酶与LDLR的表皮生长因子样重复A(EGF-A)结构域结合。我们的目标是确定干扰PCSK9和LDLR结合的化合物及其参与低密度脂蛋白受体降解的能力。为了实现我们的目标，我们集成了虚拟(计算机)筛查方法和基于细胞的分析，并确定了筛查命中。每天给喂食高脂肪/高胆固醇饮食的动物服用这些化合物中的一种，可以显著降低胆固醇水平。作为第二阶段计划的一部分，我们计划扩大和优化我们的HITS，并通过体内研究确认所选化合物防止低密度脂蛋白受体降解的能力，从而降低低密度脂蛋白水平。

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. The secreted enzyme is known to bind to the epidermal growth factor- like repeat A (EGF-A) domain of the LDLR. Our goal is to identify compounds that interfere with PCSK9 and the LDLR binding and its ability to participate in the degradation of the LDL receptor. To achieve our goal, we have integrated virtual (computer) screening methods and cell based assays and identified screening hits. Daily administration of one of these compounds to animals that are fed high fat/high cholesterol diet showed significant reduction in cholesterol level. As part of Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of the selected compounds to prevent the LDL receptor degradation, and therefore, decrease the LDL-C level using in vivo studies.