Development of myeloperoxidase inhibitors to treat atherosclerosis

开发治疗动脉粥样硬化的髓过氧化物酶抑制剂

• 批准号: 7743975
• 负责人: Richard Allan Maki
• 金额: $ 27.44万
• 依托单位: TORREY PINES PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743975
• 关键词: 3-chlorotyrosine; 3-nitrotyrosine; Acute; Alzheimer' s Disease; Arterial Fatty Streak; Astrocytes; Atherosclerosis; Bioavailable; Biological Assay; Cell physiology; Cellular Assay; Characteristics; Chloride Ion; Chlorides; Cholesterol; Chronic; Chronic Disease; Clinic; Development; Disease; Enzymes; Generations; High Density Lipoproteins; Human; Hydrogen Peroxide; Hypochlorous Acid; Impairment; In Vitro; Infection; Inflammatory; Ischemia; Lead; Lesion; Leukocytes; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low Density Lipoprotein oxidation; Marketing; Mus; Normal tissue morphology; Oxidants; Peroxidases; Phase; Proteins; Reaction; Reperfusion Therapy; Research; Screening procedure; Series; Severities; Site; Small Business Innovation Research Grant; Staging; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; chlorination; design; enzyme activity; homocitrulline; improved; in vivo; in vivo Model; inhibitor/antagonist; macrophage; mouse model; neutrophil; novel; novel therapeutics; oxidation; peroxidation; public health relevance; research study; reverse cholesterol transport; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): The overall objective of the proposed research is to develop an orally active inhibitor of MPO as a treatment for acute and chronic diseases. MPO is an abundant enzyme in leukocytes and its expression can be induced in macrophages at inflammatory sites such as atherosclerotic lesions. MPO catalyzes a reaction between chloride and hydrogen peroxide to generate hypochlorous acid, a strong oxidizing agent. Multiple lines of evidence implicate MPO in the initiation and progression of atherosclerosis through oxidation of lipoproteins, impairment of reverse cholesterol transport, and reduction of bioavailable NO. A small molecule inhibitor of MPO may be an important component in a list of therapeutic options for the treatment of chronic inflammatory diseases including atherosclerosis. In Specific Aim 1 we propose to screen a small molecule library for inhibitors of MPO. In Specific Aim 2 we propose to test the small molecule inhibitors in a variety of secondary assays designed for selectivity and cellular function before testing the small molecule in an in vivo model of atherosclerosis. PUBLIC HEALTH RELEVANCE: Myeloperoxidase is recognized as an important causative contributory agent in inflammatory diseases including atherosclerosis. An inhibitor of myeloperoxidase would provide a novel therapeutic agent that could be used as an adjunct therapy to statins and other therapeutics already on the market. The experiments outlined in this Phase I SBIR application will help set the stage for the development of a novel and safe myeloperoxidase inhibitor.

描述（由申请人提供）：拟议研究的总体目标是开发一种口服活性MPO抑制剂，作为急性和慢性疾病的治疗。MPO是白细胞中丰富的酶，它的表达可以在动脉粥样硬化病变等炎症部位的巨噬细胞中被诱导。MPO催化氯化物和过氧化氢之间的反应生成次氯酸，一种强氧化剂。多种证据表明，MPO通过脂蛋白氧化、胆固醇逆向转运受损和生物可利用NO的减少，参与动脉粥样硬化的发生和发展。MPO的一种小分子抑制剂可能是治疗包括动脉粥样硬化在内的慢性炎症性疾病的一系列治疗选择中的重要组成部分。在Specific Aim 1中，我们建议筛选MPO抑制剂的小分子文库。在Specific Aim 2中，我们建议在动脉粥样硬化的体内模型中测试小分子抑制剂之前，在设计用于选择性和细胞功能的各种二级分析中测试小分子抑制剂。公共卫生相关性：髓过氧化物酶被认为是包括动脉粥样硬化在内的炎症性疾病的重要致病因子。髓过氧化物酶抑制剂将提供一种新的治疗药物，可以作为他汀类药物和市场上已有的其他治疗药物的辅助治疗。在SBIR I期应用中概述的实验将有助于为开发一种新型安全的髓过氧化物酶抑制剂奠定基础。