HIGH-THROUGHPUT IN VIVO DISCOVERY OF CYANIDE ANTIDOTES
Cyanide poses a significant threat to human health. Smoke inhalation and industrial accidents can cause unexpected lethal exposures to cyanide. The ready availability of large quantities of cyanide also makes it a candidate for use as a chemical terror agent or chemical weapon. Preparedness to deal with unexpected mass cyanide exposures is a high priority for hospitals, first responders, and government agencies.
A few compounds with proven cyanide antidotal activity already exist. Most of these compounds have been in use for decades, and most function by forming covalent or ionic bonds with cyanide. Although the compounds provide some survival benefit in cases of borderline exposure, they suffer from low potency and difficult routes of administration. For example, sodium thiosulfate is administered intravenously and at a dose of 25 g. New generations of cyanide countermeasure are under development, including cobinamide and sulfanegen. Both molecules are derivatives of older cyanide antidotes hydroxocobalamine and 3-mercaptopyruvate, and while these molecules may prove to be more efficacious than their predecessors, their mechanisms are fundamentally the same. Potent and highly efficacious cyanide countermeasures are still needed, and methods that enable discovery of truly novel countermeasures with novel mechanisms of action are particularly attractive.
This U54 project will discover and develop cyanide countermeasures that are highly potent and function through novel mechanisms. Project 1 employs a validated, large-scale chemical screen to discover compounds that protect zebrafish from cyanide toxicity. Many of these initial hits will not possess sufficient potency or selectivity to be strong preclinical drug leads. In this project, we will use medicinal chemistry methodologies to optimize the potency of the hits discovered in Project 1. Optimized compounds will then be profiled to determine their stability, bioavailability, toxicity, and metabolic effects. These experiments will enable us to transform screening hits into potent drug leads with acceptable pharmacokinetic properties and minimal toxicities. The best of the optimized drug leads will be delivered to Project 3 for further efficacy testing in mammals