Advancing Novel Cyanide Countermeasures

我们拟建中心的总体目标是： ·交付符合BARDA关于准备就绪的氰化物反措施(S) 超前发展。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，但几种额外的下一代化合物 都在筹备中。这些发现为开发氰化物对策铺平了道路 从根本上不同于现有的对策，并有可能改变我们的应对能力 与氰化物接触有关。这款新的U54将专注于将这些发现转化为经过优化和验证的销售线索 满足高级开发和临床部署的正式要求。 除了提供这些与临床相关的产品外，我们还将做出以下贡献： ·对体内氰化物致死的各种机制的基本见解 ·系统探索新陈代谢的药理操作 ·正式描述我们平台中的不同模型之间的核心关系以及 在药物发现和开发中，在这些模式之间移动的最有效方式，目标是 开发一种可推广的方法来处理代谢毒物。

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.