Biological Chemistry and Pharmacology of Nitroxyl (HNO)

描述（由申请人提供）：硝酰基（HNO）是一种具有独特和重要生物活性的新型氮氧化物。其最具挑衅性和治疗新颖的属性之一是其治疗心力衰竭的潜力。HNO具有用于此目的的几乎完美的生物活性组合。该提案“氮氧自由基（HNO）的生物化学和药理学”旨在开发一系列HNO供体分子，用作潜在的候选药物以及研究工具。将在体外系统中检查这些分子的作用，以评估其作为药理学试剂的潜力。此外，我们打算评估可能的机制，HNO的行为。更具体地说，我们将评估信号分子过氧化氢（H2 O2）和HNO之间的关系。其基本原理是基于HNO和H2 O2的几乎相同的生化靶标、其相关和重叠的生物活性以及HNO可以显著改变H2 O2代谢的可能性。总之，该提议用于1）开发用于实验室的新型和重要的HNO供体，并最终作为可能的药物开发的基础，和2）检查它们作为血管剂的活性和H2 O2在这方面的可能作用。 公共卫生相关性：心力衰竭是美国65岁以上人群住院的主要原因。在美国，每年有超过500万人被诊断患有心力衰竭，超过30万人死亡。目前，心力衰竭的治疗相对无效，因此开发其他治疗方法是一个重要目标。据所有人说，硝酰基（HNO）具有治疗心力衰竭的近乎完美的活性谱，并且与大多数其他药物在机制上无关。此外，已提出HNO可用于预防缺血再灌注损伤，甚至用于治疗酒精中毒。该提案旨在合成HNO供体，用作可能的药物和/或研究工具。此外，HNO活性的机制将被检查，并建立其与其他重要的信号系统的关系。

DESCRIPTION (provided by applicant): Nitroxyl (HNO) is a novel nitrogen oxide species with unique and important biological activity. One of its most provocative and therapeutically novel attributes is its potential for the treatment of heart failure. HNO possesses an almost perfect combination of biological activities for this purpose. The proposal "The Biological Chemistry and Pharmacology of Nitroxyl (HNO)" intends to develop a series of HNO- donor molecules for use as potential drug candidates as well as research tools. The actions of these molecules will be examined in in vitro systems to assess their potential as pharmacological agents. Further, we intend to assess possible mechanisms by which HNO acts. More specifically, we will assess the relationship between the signaling molecule hydrogen peroxide (H2O2) and HNO. The rationale for this is based on the near identical biochemical targets for HNO and H2O2, their related and overlapping biological activities and the likelihood that HNO can dramatically alter H2O2 metabolism. In all, this proposal serves to 1) develop novel and important HNO donors for use in the laboratory and, eventually, to serve as the basis for possible drug development and 2) examine their activity as vascular agents and the possible role of H2O2 in this regard. PUBLIC HEALTH RELEVANCE: Heart failure is a leading cause of hospitalization of people over 65 in the United States. Over 5 million people have been diagnosed with heart failure and over 300,000 people die annually in the US. Currently, the treatments for heart failure are relatively ineffective making development of other treatments an important objective. By all accounts, nitroxyl (HNO) possesses a near perfect spectrum of activity for the treatment of heart failure and is mechanistically unrelated to most other drugs. Moreover, HNO has been proposed to be useful for preventing ischemia-reperfusion injury and even for the treatment of alcoholism. This proposal intends to synthesize HNO donors for use as possible drugs and/or research tools. Also, the mechanism of HNO activity will be examined and its relationship with other important signaling systems established.