Project 1

This project proposes the discovery of novel cyanide countermeasures in phenotype-based chemical screens in zebrafish.  In prior work we have developed a zebrafish model of cyanide poisoning with stereotypical toxicities including bradycardia, neuronal mecrosis, and death.  We have adapted this model for HYS, and performed proof of concept studies as a screen for compounds that reproducible rescue zebrafish from lethal cyanide exposure. Specific Aims of this project are:

• To develop and validate additional zebrafish assays for specific vulnerable populations
• To continue ongoing screening of additional diverse small molecule libraries
• To systematically prioritize screen hits for development as optimized leads.

This project will generate a range of novel hits for subsequent optimization through SAR and medicinal chemistry in Project 2.  Each of these hits will meet criteria for potency and will also satisfy initial screens for toxicity and mode of action profiling.  Analog series generated in Project 2 will also be fed back to Project 1 for initial efficacy and toxicity screens.  Similarly, specific biological questions on the therapeutic or toxic effects of drug metabolites identified in Project 3, as well as combination screens with existing agents will be undertaken in Project 1.  Project 1 will use Core C for initial mode of action profiling, and for characterization of the distinctive metabolic responses to cyanide across different age groups.  This will exploit the compressed developmental timeline exhibited in the zebrafish, and will allow us to assess the interaction between cyanide and various countermeasures in both acute and chronic contexts.