A Discovery and Development Pipeline for Cyanide Countermeasures

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Cyanide is an archetypal chemical threat. This powerful natural toxin is encountered in many different settings and potential exposures range from industrial accidents to major terrorist attacks. Cyanide has devastating consequences. Higher quantities lead rapidly to seizures, cardiovascular collapse and death, while lower doses are associated with substantial long-term morbidity including debilitating central nervous system injury. Currently available antidotes simply do not match the complexity or scale of the potential mass casualty threat scenarios, and there is an urgent need to develop novel countermeasures. The major aims of this CounterACT Center of Excellence proposal are 1) to identify novel classes of cyanide countermeasure using unbiased approaches in a validated zebrafish model system, 2) to explore in vivo the structure activity relationships (SAR) of these novel countermeasure classes and using medicinal chemistry generate a series of optimized lead compounds and 3) to validate these optimized leads in established murine and rabbit models of cyanide toxicity. Together these individual interdisciplinary aims are focused around the overarching goal of this collaborative U54 application: The identification of at least 3 novel cyanide countermeasures ready to move directly to formal preclinical testing and Phase I clinical studies at the completion of the current application. Successful generation of three validated countermeasures using this pipeline will not only lay the foundation for parallel work in preclinical development (through the CounterACT Preclinical Development Facility or CPDF as outlined below) and for subsequent clinical development of these compounds (in a logical extension of the current proposal), but will also form a generalizable approach for the accelerated development of countermeasures to any existing or emerging chemical threat.