Structure-Based Search for Novel Antihypercholestrolemic Agent

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，高胆固醇水平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，并且具有非常高的过早心血管疾病风险。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杆菌样keexin 9 （PCSK9）。PCSK9控制肝脏中LDL受体（LDLR）的降解，从而有助于胆固醇稳态。PCSK9作为前体蛋白合成，在原结构域和催化结构域之间进行加工。这一过程是PCSK9分泌和发挥其生物活性所必需的。我们的目标是确定阻止PCSK9加工的化合物，从而阻止其分泌和参与LDL受体降解的能力。为了实现第一阶段的目标，我们将虚拟（计算机）筛选方法与基于细胞的测定相结合，从而确定了五个筛选点。作为II期计划的一部分，我们计划扩大和优化我们的靶点，并通过原位和体内研究确认所选化合物稳定ldl - lr和降低LDL-C水平的能力。

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.