Nitric Oxide Donor Compounds for the Treatment of Hemolytic Conditions

描述（由申请人提供）：一氧化氮（NO）是一种内皮来源的松弛因子；它在血管周围的内皮细胞中合成，发出放松平滑肌和增加血液流动的信号。血红蛋白（Hb）以接近扩散限制的速率积极清除NO。在正常生理情况下，由于血液中红细胞的区隔化，血红蛋白清除NO的能力降低。一些疾病，包括溶血性贫血，如镰状细胞病和阵发性夜间血红蛋白尿（PNH），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Hb释放到血浆室，有效清除NO。这种增加的NO清除导致许多并发症，导致发病率和死亡率。通过吸入一氧化氮已被证明可以恢复正常的一氧化氮反应性，并有望作为溶血性疾病的治疗方法。然而，一氧化氮吸入作为慢性治疗手段并不实用。该项目的目标是测试（并在一定程度上合成）最终可以静脉注射或口服治疗溶血性疾病的化合物。与许多治疗性化合物不同，这里提出的化合物将是细胞不渗透的，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NONOates （NO供体）、nitroxyl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和激光衍射变形性测定。理想的化合物应优先与无细胞（而不是红细胞包裹）的血红蛋白发生反应，反应时间允许其在血浆寿命内起作用。

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.