Nitric Oxide Donor Compounds for the Treatment of Hemolytic Conditions

用于治疗溶血病症的一氧化氮供体化合物

• 批准号: 7387531
• 负责人: DANIEL B KIM-SHAPIRO
• 金额: $ 16.16万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-08 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387531
• 关键词: Amines; Biological Assay; Biological Availability; Biology; Blood; Blood Vessels; Blood flow; Breathing; Canis familiaris; Cardiopulmonary Bypass; Cells; Chronic; Condition; Data; Diffusion; Electron Spin Resonance Spectroscopy; Encapsulated; End Point; Endothelium; Erythrocytes; Goals; Hemoglobin; Hemolysis; Hemolytic Anemia; Hemolytic-Uremic Syndrome; Kinetics; Lasers; Lead; Letters; Lipids; Malaria; Measures; Methodology; Methods; Modeling; Morbidity - disease rate; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrites; Paroxysmal Hemoglobinuria; Pathology; Patients; Physiology; Plasma; Production; Rate; Reaction; Reactive Oxygen Species; Relaxation; Research Personnel; Sickle Cell Anemia; Signal Transduction; Small Business Technology Transfer Research; Smooth Muscle; Testing; Thalassemia intermedia; Therapeutic; Thrombotic Thrombocytopenic Purpura; Time; Toxic effect; absorption; adduct; diazeniumdiolate; experience; mortality; nitrate; nitroxyl; novel strategies; oxidation; rat Piga protein; success; tool

DESCRIPTION (provided by applicant): Nitric oxide (NO) is an endothelial derived relaxation factor; it is synthesized in the endothelium surrounding blood vessels and signals to relax smooth muscles and increase blood flow. Hemoglobin (Hb) actively scavenges NO at nearly diffusion-limited rates. In normal physiology, NO scavenging by Hb is reduced due to compartmentalization in red blood cells in the blood. Several diseased conditions including hemolytic anemias such as sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and cardiopulmonary bypass result in release of Hb into the plasma compartment which efficiently scavenges NO. This increased NO scavenging leads to a host of complications contributing to morbidity and mortality. Administration of NO through inhalation has been shown to restore normal NO responsiveness and shows promise as a treatment for hemolytic conditions. However, NO inhalation is not practical as a means of chronic treatment. The goal of this project is to test (and to some extent synthesize) compounds that can eventually be taken intravenously or orally to treat hemolytic conditions. Unlike many therapeutic compounds, the ones proposed here would be cell-impermeable, acting in the plasma compartment so as to react preferentially with cell-free Hb and thereby inactivate its NO scavenging ability. Lead compounds to be studied include NONOates (NO donors), nitroxyl donors and possibly nitrated lipids and nitrites. A variety of biophysical methods are proposed to test the potential efficacy of the synthesized compounds including absorption and electron paramagnetic resonance spectroscopy and laser diffraction deformability assays. An ideal compound would react preferentially with cell-free (as opposed to red blood cell encapsulated) Hb in a time frame that would allow it to act within its plasma lifetime.

描述（由申请人提供）：一氧化氮（NO）是一种内皮衍生的松弛因子；它是在血管周围的内皮细胞中合成的，并发出信号以放松平滑肌并增加血流量。血红蛋白 (Hb) 以接近扩散限制的速率主动清除 NO。在正常生理学中，由于血液中红细胞的区室化，Hb 清除 NO 的能力会减少。多种疾病，包括溶血性贫血，如镰状细胞病和阵发性睡眠性血红蛋白尿 (PNH)、中间型地中海贫血、疟疾、血栓性血小板减少性紫癜、溶血性尿毒症综合征和体外循环，导致血红蛋白释放到血浆室中，从而有效清除一氧化氮。 NO 清除的增加会导致一系列并发症，导致发病率和死亡率。通过吸入给予 NO 已被证明可以恢复正常的 NO 反应性，并有望作为溶血性疾病的治疗方法。然而，吸入一氧化氮作为慢性治疗手段并不实用。该项目的目标是测试（并在某种程度上合成）最终可以静脉内或口服治疗溶血性疾病的化合物。与许多治疗化合物不同，这里提出的化合物是细胞不可渗透的，在血浆室中起作用，以便优先与无细胞的 Hb 反应，从而使其 NO 清除能力失活。要研究的先导化合物包括 NONOate（NO 供体）、硝酰基供体以及可能的硝化脂质和亚硝酸盐。提出了多种生物物理方法来测试合成化合物的潜在功效，包括吸收和电子顺磁共振光谱以及激光衍射变形分析。理想的化合物会在允许其在血浆寿命内发挥作用的时间范围内优先与无细胞（而不是封装的红细胞）血红蛋白发生反应。