Assessment of the Chemical Biology of HNO via New Donors

描述(申请人提供)：一氧化氮(NO)生物学是生物医学科学中最多产的领域之一，影响了我们对基本生理学和疾病病因学的理解。NO是一种独特的内源性信号转导因子，因为它的化学成分是其生物学功能的唯一最重要的决定因素。这一领域的研究主要集中在NO和相关的氧化物种上；然而，最近的注意力集中在还原物种氮氧基(HNO)上。比较研究表明，对NO和HNO供体的化学反应和生物反应往往是离散的。我们的长期目标是利用这种多样性，同时彻底了解氮氧化物的化学生物学，以提供疾病治疗。HNO与内源信号的相关性仍然是一个有争议的问题，部分原因是对其基础化学的了解较差，以及定义其在生物学中的作用的技术有限。此外，由于快速的自我消耗，HNO必须就地生产。最常见的给体是氮氧化物，Na2N2O，已被证明在启动HNO独特的化学性质和药理作用的研究中具有无价的价值。然而，只有开发具有适应能力的骨干的捐赠者来补充已经存在的NO的捐赠者，才有可能对HNO进行治疗性开发。这项建议的具体目标是1)设计、合成和表征基于有机骨架的新型HNO供体；2)利用该供体文库和现有的HNO供体来阐明HNO的化学生物学的基本方面；以及3)确定特定的生物靶点。这些目标的完成将扩大我们对HNO的化学及其在生物学中的作用的理解，并可能对心力衰竭、心肌梗死和中风的治疗产生直接影响。此外，新的生物靶点，如锌指和非血红素铁中心，可能会被揭示，这可能会建议其他治疗干预措施。

DESCRIPTION (provided by applicant): The biology of nitric oxide (NO) is 1 of the most prolific fields in biomedical science and has impacted our understanding of both basic physiology and disease etiology. NO is a unique endogenous signaling agent since its chemistry is the single most important determinant of its biological function. Research efforts in this field have primarily focused on NO and related oxidized species; however, recent attention has been devoted to the reduced species nitroxyl (HNO). Comparative studies have demonstrated that the chemistry and thus the biological responses to NO and HNO donors are often discrete. Our long-term goal is to utilize this diversity in conjunction with a thorough understanding of the chemical biology of nitrogen oxides to provide disease treatments. The relevance of HNO to endogenous signaling is still a matter of debate, in part due to a poor understanding of its basic chemistry and to limited techniques to define its role in biology. Further, due to rapid self-consumption, HNO must be produced in situ. The most common donor is a nitrogen oxide salt, Na2N2O3, which has proven to be invaluable in the initiation of the study of the unique chemical properties and pharmacological effects of HNO. However, therapeutic exploitation of HNO will only be possible with development of donors with adaptable backbones to complement those that already exist for NO. The specific aims of this proposal are 1) to design, synthesize and characterize novel HNO donors based on organic backbones; 2) to utilize this donor library and existing HNO donors to elucidate fundamental aspects of the chemical biology of HNO; and 3) to identify specific biological targets. Completion of these aims will expand our understanding of the chemistry of HNO and its roles in biology and may have direct implications for the treatment of heart failure, myocardial infarct and stroke. Additionally, new biological targets, such as zinc fingers and non-heme iron centers, are likely to be revealed, which may suggest other therapeutic interventions.