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.
Cyanide remains one of the most important chemical threats as a result of terrorism and industrial or other accidents. Current countermeasures, the majority of which are over 90 years old, are inadequate for the most likely threat scenarios. This program builds on our recent identification of three new classes of countermeasure, defining their mechanisms of action and moving the most promising class members to preclinical testing.
