Drugs targeting intact lipoprotein receptors

针对完整脂蛋白受体的药物

• 批准号: 6736022
• 负责人: Bruce S Sachais
• 金额: $ 17.11万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736022
• 关键词: antireceptor antibody; apolipoproteins; atherosclerosis; biosensor device; biotechnology; cardiovascular disorder chemotherapy; drug discovery /isolation; enzyme linked immunosorbent assay; human tissue; lead; low density lipoprotein receptor; membrane proteins; membrane structure; protein purification; protein structure; radiotracer; receptor binding; receptor expression; technology /technique development; very low density lipoprotein

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.

描述（由申请人提供）：心血管疾病（CVD）是美国排名第一的杀手。不利的脂蛋白谱是动脉粥样硬化的主要危险因素，这种病情是CVD死亡人数超过70％的疾病。绝大多数药物疗法（他汀类药物）针对一个分子靶标（HMG-COA还原酶）。这些药物的目的是改善脂蛋白谱，从而改善患者的心血管风险。但是，最佳的心血管降低通常需要组合疗法，并且此类组合的选择受到限制。在与CVD斗争中需要针对新目标的新药。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，针对这些受体的药物可能对降低心血管风险有益。但是，这些受体在有意义的药物靶标测定中很难研究。整体分子已经开发了一种技术，即脂肪颗粒，该技术使膜蛋白可以从细胞的表面纯化，同时保持其结构完整性。在此I阶段应用中，我们建议创建含有全长低密度脂蛋白受体（LDL-R）的脂质颗粒。我们将以两个特定目的创建，表征和测试LDL-R脂蛋白。特定目标1：构建和测试含有LDL-R的脂质颗粒。在此目标中，我们将创建LDL-R脂质颗粒，并将它们与使用标准ELISA和放射性技术技术的替代受体试剂（在活细胞中表达的受体和可溶性受体片段表达）进行比较。特定目标2：创建和验证基于生物传感器的LDL-R脂质颗粒分析。在此目标中，我们将在光学生物传感器平台上使用LDL-R脂质颗粒，以测量配体结合动力学。

项目成果

Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia.

• DOI: 10.1182/blood-2012-01-406801
• 发表时间: 2012-06
• 期刊: Blood
• 影响因子: 20.3
• 作者: B. Sachais;A. Rux;D. Cines;S. Yarovoi;Lee Garner;S. Watson;Jillian L. Hinds;J. Rux