SBIR-STTR Award

This is a proposal to develop inhibitors of the lethal factor (LF) zinc protease that is responsible for the deadly effects of Anthrax. The Structural Bioinformatics group intend to use homology modeling and Monte Carlo simulations to develop structural models and consensus sequences for peptides that are known to be cleaved by the lethal factor. They will then use other computational techniques to select hydroxamates from a virtual library as potential inhibitors. Approximately 40 compounds will be prepared, and tested for their ability to inhibit LF. The significant milestone proposed for Phase I is to find an LF inhibitor with a Ki <1 uM; that would be 300 times better than the best inhibitor cited in this proposal (which is also a hydroxamate)

Bacillus anthracis, the cause of Anthrax, poses a considerable danger because of its potential use in bioterrorism. Respiratory anthrax infections are almost invariably fatal despite antibiotic treatment. Existing vaccines provide no protection against certain strains of B. anthracis. A small drug-like molecule that could inhibit the action of lethal factor, the zinc metalloprotease responsible for the lethal effects of bacillus anthracis, could provide significant protection against anthrax. Using patented and proprietary protein structure-based methods, Structural Bioinformatics Inc. extracted 3D-pharmacophore information from the computationally modeled LF substrate MAPKK1 during Phase I. After synthesis based on this pharmacophore, seven compounds with 1C50 <50 mu M were obtained, including one with 1C50 = 2.7 mu M. The goal of Phase Il is to identify noncytotoxic LF inhibitors that inhibit the ability of anthrax dual toxin (LF + anthrax protective antigen) to kill monocytic cells, with IC50 < 100 nM, and >100-fold selectivity against LF versus human metalloenzymes. To this end, refined pharmacophores and docking models will be developed by applying SBl's technology to crystal structures data for LF and LF/inhibitor complexes. The long-term goal of this project is to develop a clinically useful small molecule that blocks the toxic effects of bacillus anthracis.

Thesaurus Terms:
Bacillus anthracis, computer simulation, lethal gene, mitogen activated protein kinase, protease inhibitor, protein sequence, structural biology, structural model anthrax, biomarker, chemical synthesis, cytotoxicity, endopeptidase, hydroxamate, molecular biology information system X ray crystallography