Biological Chemistry and Pharmacology of Nitroxyl (HNO)

描述（申请人提供）：硝基（Nitroxyl， HNO）是一种新型氮氧化物，具有独特而重要的生物活性。它在治疗心力衰竭方面的潜力是最具挑战性和最新颖的特性之一。为此目的，HNO具有几乎完美的生物活性组合。“硝基（Nitroxyl， HNO）的生物化学和药理学”提案旨在开发一系列HNO供体分子，作为潜在的候选药物和研究工具。这些分子的作用将在体外系统中进行检查，以评估它们作为药理学制剂的潜力。此外，我们打算评估HNO作用的可能机制。更具体地说，我们将评估信号分子过氧化氢（H2O2）和HNO之间的关系。其基本原理是基于HNO和H2O2几乎相同的生化靶标，它们相关和重叠的生物活性，以及HNO可能显著改变H2O2代谢。总而言之，该提案旨在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；2)研究它们作为血管剂的活性以及H2O2在这方面的可能作用。

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.