INHIBITORS OF ANTHRAX LETHAL FACTOR METALLOPROTEINASE

DESCRIPTION (provided by applicant): This proposal outlines a novel approach towards the development of a therapeutic agent to treat anthrax infection by inhibiting the intracellular actions of lethal factor, the main virulence factor expressed in Bacillus anthracis infected organisms. While antibiotics are effective in treating early-stage anthrax infection by "wild-type" Bacillus anthracis strains, they are ineffective in treating infection at later stages, infection by antibiotic-resistant strains or infection with other modified bacteria or viruses engineered to express lethal factor. This SBIR Phase I feasibility study includes the development of screening assays (primary peptide cleavage and secondary macrophage-based cytotoxicity) for evaluation of unique metalloproteinase inhibitor libraries already synthesized at Hawaii Biotechnology Group, Inc. under a current contract from the Department of Defense. The most interesting lethal factor inhibitors derived from this study (approx. 3-20 compounds) will be optimized in Phase II according to standard pharmaceutical strategies with which we have significant experience. The resulting drug-like molecules will have efficacy in treating lethal factor delivered to the organism by "wild-type" Bacillus anthracis strains or other pathogens. In addition to the potential large commercial market for anthrax therapies, selected compounds will be tested in models for other bacteria as well as cancer and immunoinflammatory diseases.