Drugs targeting intact lipoprotein receptors

描述（由申请人提供）：心血管疾病（CVD）是美国的头号杀手。不利的脂蛋白谱是动脉粥样硬化的主要危险因素，动脉粥样硬化是超过70%的CVD死亡的基础。绝大多数药物治疗（他汀类药物）针对一个分子靶点（HMG-CoA还原酶）。这些药物的目的是改善脂蛋白谱，从而降低患者的心血管风险。然而，最佳的心血管风险降低往往需要联合治疗，这种组合的选择是有限的。在对抗CVD的斗争中，需要针对新靶点的新药。脂蛋白受体（即LDL-R、LRP、SR-BI）在动脉粥样硬化的发展中起着核心作用，靶向这些受体的药物可能有助于降低心血管风险。然而，这些受体很难在有意义的药物靶向测定中进行研究。Integral Molecular开发了一种技术，即脂质颗粒，它使膜蛋白能够从细胞表面纯化出来，同时保持其结构完整性。在这个I期申请中，我们建议创建包含全长低密度脂蛋白受体（LDL-R）的脂质颗粒。我们将创建，表征和测试LDL-R脂蛋白在两个特定的目标。具体目的1：构建和测试含有LDL-R的脂质颗粒。为此，我们将创建LDL-R脂质颗粒，并使用标准ELISA和放射性配体技术将其与替代受体试剂（活细胞中表达的受体和可溶性受体片段）进行比较。具体目标2：创建并验证基于生物传感器的LDL-R脂质颗粒分析。为此，我们将在光学生物传感器平台上使用LDL-R脂质颗粒，目的是测量配体结合动力学。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the number one killer in the United States. An unfavorable lipoprotein profile is the primary risk factor for atherosclerosis, the condition that underlies over 70% of CVD deaths. The vast majority of medical therapy (statins) is directed toward one molecular target (HMG-CoA reductase). The goal of these drugs is to improve the lipoprotein profile and consequently the cardiovascular risk of the patient. However, optimal cardiovascular risk reduction often requires combination therapy, and the choices for such combinations are limited. New drugs directed at novel targets are needed in the fight against CVD. Lipoprotein receptors (i.e. LDL-R, LRP, SR-BI) play a central role in the development of atherosclerosis, and drugs targeted against these receptors may be beneficial in cardiovascular risk reduction. However, these receptors are difficult to study in meaningful drug target assays. Integral Molecular has developed a technology, the lipoparticle, which enables membrane proteins to be purified away from the surface of a cell while maintaining their structural integrity. In this Phase I application, we propose to create lipoparticles containing the full-length low-density lipoprotein receptor (LDL-R). We will create, characterize and test LDL-R lipoproteins in two specific aims. Specific Aim 1: Construct and test lipoparticles containing LDL-R. In this aim, we will create LDL-R lipoparticles and compare them to alternative receptor reagents (receptor expressed in live cells, and soluble receptor fragments) using standard ELISA and radioligand techniques. Specific Aim 2: Create and validate biosensor-based analysis of LDL-R lipoparticles. In this aim, we will use LDL-R lipoparticles on the optical biosensor platform with the goal of measuring ligand-binding kinetics.