Assessment of the Chemical Biology of HNO via New Donors

描述（由申请人提供）：一氧化氮（NO）生物学是生物医学科学中最多产的领域之一，它影响了我们对基础生理学和疾病病因学的理解。一氧化氮是一种独特的内源性信号剂，其化学成分是其生物学功能的最重要决定因素。该领域的研究工作主要集中在NO和相关的氧化物质上；然而，近年来人们对还原性物种硝基（nitroxyl， HNO）的研究越来越关注。比较研究表明，化学反应和因此对NO和HNO供体的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，结合对氮氧化物化学生物学的透彻理解，提供疾病治疗。HNO与内源性信号的相关性仍然是一个有争议的问题，部分原因是对其基本化学成分的理解不足，以及确定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必须在原位生产。最常见的供体是一种氮氧化物盐，Na2N2O3，它已被证明在研究HNO独特的化学性质和药理作用的开始是无价的。然而，治疗性利用一氧化氮只有通过培养具有适应性骨干的供体来补充已经存在的一氧化氮才能实现。本课题的具体目标是：1)设计、合成和表征基于有机骨架的新型HNO供体；2)利用该供体库和现有的HNO供体来阐明HNO化学生物学的基本方面；3)识别特定的生物靶点。这些目标的完成将扩大我们对HNO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有直接的影响。此外，新的生物学靶点，如锌指和非血红素铁中心，可能会被发现，这可能会提出其他治疗干预措施。

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.