Nitric Oxide Donor Compounds for the Treatment of Hemolytic Conditions

描述（由申请人提供）：一氧化氮（NO）是一种内皮源性舒张因子;它在血管周围的内皮中合成，并发出舒张平滑肌和增加血流量的信号。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对NO的清除减少。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症（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心肺转流术在内的几种疾病状况导致Hb释放到血浆室中，其有效地清除NO。这种增加的NO清除导致大量并发症，导致发病率和死亡率。通过吸入给予NO已显示出恢复正常的NO反应性，并显示出作为溶血性病症的治疗的前景。然而，NO吸入作为慢性治疗的手段是不实用的。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。与许多治疗化合物不同，本文提出的化合物将是细胞不可渗透的，在血浆室中起作用，以便优先与无细胞Hb反应，从而增强其NO清除能力。待研究的先导化合物包括NONOates（NO供体）、硝酰基供体和可能硝化的脂质和亚硝酸盐。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法和激光衍射变形性测定。理想的化合物将优先与无细胞（与包封的红细胞相反）Hb在允许其在血浆寿命内起作用的时间范围内反应。

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.