Assessment of the Chemical Biology of HNO via New Donors

通过新捐助者评估 HNO 的化学生物学

• 批准号: 7252062
• 负责人: Katrina M. Miranda
• 金额: $ 22.52万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252062
• 关键词: Amines; Angeli' s salt; Attention; Binding; Biological; Biological Process; Biology; Biomedical Research; Cardiovascular Diseases; Cell physiology; Chemicals; Chemistry; Class; Classification; Comparative Study; Complement; Condition; Consumption; Data; Development; Dimerization; Disease; Environment; Etiology; Exhibits; Exposure to; Free Radicals; Functional disorder; Future; Goals; Heart failure; Heme Iron; In Situ; Intervention; Investigation; Libraries; Measures; Metalloproteins; Metals; Methods; Modification; Molecular; Myocardial Infarction; Nitric Oxide; Nitrites; Nitrogen; Nitrogen Oxides; Oxidation-Reduction; Pathway interactions; Pharmacology; Physiological; Physiology; Process; Production; Property; Proteins; Rate; Research; Research Personnel; Role; Science; Series; Signal Pathway; Signal Transduction; Standards of Weights and Measures; Stroke; Sulfhydryl Compounds; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Validation; Vertebral column; Zinc Fingers; aqueous; base; chemical property; controlled release; design; diazeniumdiolate; infancy; nitroxyl; novel; organic base; programs; response; tool

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.

描述（由申请人提供）：一氧化氮（NO）的生物学是生物医学科学中最多产的领域之一，影响了我们对基础生理学和疾病病因学的理解。 NO 是一种独特的内源性信号剂，因为它的化学性质是其生物功能的最重要的决定因素。该领域的研究工作主要集中在 NO 和相关的氧化物质；然而，最近的注意力集中在还原态硝酰基 (HNO) 上。比较研究表明，对 NO 和 HNO 供体的化学反应以及生物反应通常是离散的。我们的长期目标是利用这种多样性以及对氮氧化物化学生物学的透彻了解来提供疾病治疗。 HNO 与内源信号传导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了解甚少，并且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，硝酸必须就地生产。最常见的供体是氮氧化物盐 Na2N2O3，事实证明，它对于开展 HNO 独特化学性质和药理作用的研究具有无价的价值。然而，只有开发出具有适应性骨架的供体来补充 NO 已有的骨架，HNO 的治疗利用才有可能。该提案的具体目标是 1) 设计、合成和表征基于有机主链的新型 HNO 供体； 2) 利用该供体库和现有的 HNO3 供体来阐明 HNO3 化学生物学的基本方面； 3）确定特定的生物靶标。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、心肌梗塞和中风的治疗产生直接影响。此外，新的生物靶标，例如锌指和非血红素铁中心，可能会被发现，这可能会建议其他治疗干预措施。