The possibility of catastrophic military or civilian cyanide exposure as a result of a terrorist attack or an industrial accident, is a major challenge for our defense agencies and healthcare infrastructure (1-3) New, effective countermeasures are urgently required. In addition, there is a clear need for a platform capable of moving rapidly from the identification of novel threats through animal modeling to efficient countermeasure discovery. We propose to create an integrated pipeline for the discovery and development of novel candidate countermeasures for cyanide toxicity through the process of therapeutic development toward regulatory approval. We have developed a zebrafish model in which exposure to cyanide causes stereotypical toxicities including bradycardia, neuronal necrosis, and death. Traditional cyanide antidotes are pooriy suited to mass-casualty exposures, but offered key benchmarks for our validation of the zebrafish as an animal model for chemical countermeasure development. In prior work, funded through the NIH CounterACT Program, we have developed and validated a zebrafish model of cyanide toxicity, adapted this model for high-throughput screening, and in 'proof of concept'studies have performed a screen for compounds that reproduclbly rescue zebrafish from lethal cyanide exposure. In this screen (to date of >35,000 compounds), we were able to identify 26 small molecules that rescue cyanide toxicity at concentrations <1uM. These compounds are now moving to Project 2 in order to identify and prioritize optimized lead compounds for subsequent development as outlined in this integrated U54 Center. Optimized leads will in turn be moved to Project 3 where they will be tested in validated murine and rabbit models. We propose to continue our efforts to furnish novel countermeasure classes, through ongoing studies of compounds already identified, the development of refined zebrafish models for specific vulnerable populations, the continued screening of diverse chemical libraries to identify novel hits and the development of scalable strategies for the prioritization of large numbers of emerging hits. In principle, the approach we have outlined is potentially generalizable for any chemical threat whose toxic effects can be modeled in the zebrafish.
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|Peterson, Randall T; Macrae, Calum A (2013) Changing the Scale and Efficiency of Chemical Warfare Countermeasure Discovery Using the Zebrafish. Drug Discov Today Dis Models 10:|