Countermeasures for bioterrorism typical target the pathogen as opposed to the host. However, pathogens with drug-resistant characteristics are readily produced, either by naturally occurring selection or deliberate engineering by terrorists. We propose a novel countermeasure approach involving design of multi-purpose inhibitors of cellular host factors that pathogens depend on for their virulence. Because these inhibitors are equally effective against both the natural and the re-engineered pathogens, they will be a valuable addition to the existing biodefense armamentarium. We propose to use Anthrax as a well-established model of a Class A pathogen. Bacillus anthracis is deadly in part because of the toxin it secretes. To become active, Protective Antigen (PA), an essential delivery component of lethal Anthrax Toxin, requires furin-family proteases for proteolytic processing, similar to several additional bacterial virulence factors and viruses, including hemorrhagic fever flaviviruses and avian influenza H5N1 (bird flu). Once inside the cytosol of host cells, the Anthrax Toxin stimulates activation of NALP1, inducing apoptosis. NALP1 is a member of the NLR family, proteins that form complexes known as """"""""inflammasomes,"""""""" which activate caspase-family proteases. Genetic studies of mice indicate that NALP1 is required for Anthrax Toxin-induced macrophage apoptosis and in vivo susceptibility to lethal disease in the setting of Bacillus anthracis exposure. We propose to generate small-molecule chemical inhibitors of furin-family proteases and NLR-family caspase activators. To this end, we have assembled a multi-disciplinary, collaborative team with expertise in high-throughput chemical library screening, medicinal chemistry, and drug discovery; we have also produced several prototype assays for high throughput screening, with the aim of generating chemical leads against furin- and NALP-family proteins. These leads will be optimized for potency, selectivity, and pharmacological properties, and then tested in rodent models of Anthrax. The resulting chemical inhibitors of furin- and NALP1-family host proteins will provide lead compounds for potential clinical development. ? ? ?
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