Advancing novel cyanide countermeasures

推进新型氰化物对策

• 批准号: 10241493
• 负责人: Calum A. MacRae
• 金额: $ 319.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241493
• 关键词: Accidents; Achievement; Advanced Development; Antidotes; Clinic; Clinical; Combined Modality Therapy; Cyanides; Development; Dimethyl Sulfoxide; Elements; Family suidae; Formulation; Funding; Generations; Goals; Human; Industrialization; Injections; Investments; Lead; Metabolic; Metabolism; Modeling; Mus; Oryctolagus cuniculus; Pharmaceutical Chemistry; Pharmacology; Preclinical Testing; Readiness; Research; Research Personnel; Rewards; Science; Technology; Terrorism; Toxic effect; Toxicology; Translating; Translations; Work; Zebrafish; chemical threat; clinically relevant; design; drug development; drug discovery; glyoxylate; high throughput screening; in vivo; innovation; insight; meetings; member; metabolic poison; metabolomics; next generation; novel; product development; programs; small molecule libraries

The overarching objective of our proposed center is: · The delivery of cyanide countermeasure(s) that meet the BARDA definition of readiness for advanced development. In prior work within our consortium, we have discovered new compound classes that can counteract the effect of cyanide. Foremost among these are the multivalent cyanide scavenger hexachloroplatinate and the metabolic modulator glyoxylate, but several additional next-generation compounds are in the pipeline. These discoveries pave the way for development of cyanide countermeasures that are fundamentally different from existing countermeasures and have the potential to transform our ability to respond to cyanide exposures. This new U54 will focus on translating these discoveries into optimized, validated leads meeting the formal requirements for advanced development and clinical deployment. In addition to the delivery of these clinically relevant products, we will also contribute: · Fundamental insights into the full range of mechanisms of cyanide-induced lethality in vivo · Systematic exploration of the pharmacological manipulation of metabolism · Formal characterization of the core relationships between the different models in our platform and of the most efficient ways to move between these models in drug discovery and development, with the goal of developing a generalizable approach to metabolic poisons.

我们建议的中心的总体目标是： ·提供符合巴尔达准备就绪定义的氰化物对策， 先进的发展。在我们联盟之前的工作中，我们发现了新的复合类， 可以抵消氰化物的影响其中最重要的是多价氰化物清除剂 六氯铂酸盐和代谢调节剂乙醛酸盐，但其他几种下一代化合物 正在筹备中这些发现为氰化物对策的发展铺平了道路， 与现有的反制措施有着根本的不同，并有可能改变我们的应对能力 氰化物暴露。这款全新的U54将专注于将这些发现转化为经过优化和验证的潜在客户 满足高级开发和临床部署的正式要求。 除了提供这些临床相关产品外，我们还将为以下方面做出贡献： ·对氰化物诱导的体内致死性的全方位机制的基本见解 ·系统探索代谢的药理学操作 ·正式描述我们平台中不同模型之间的核心关系， 在药物发现和开发中在这些模型之间移动的最有效方法，目标是 发展出一种可推广的代谢毒物的方法。