Small Molecule Inhibitors of C. Perfringens Epsilon-Toxin

The overall goal of this SBIR Phase I proposal is to find compounds that inhibit C. perfringens epsilon-toxin action using a novel approach for the inactivation of pore-forming toxins developed at Innovative Biologics, Inc. It is based on the blocking of the target pore with molecules having the same symmetry as the pore itself.<P> Previously, we demonstrated that per-substituted derivatives of beta-cyclodextrin (beta-CD) having a sevenfold symmetry could block the heptameric pore formed by Bacillus anthracis protective antigen (PA) and were protective against anthrax lethal toxin action in cell-based assays and in animals tests.<P> Since C. perfringens epsilon -toxin forms a heptameric trans-membrane pore similar to the PA pore, we propose to screen our library of per-substituted beta-CD derivatives for inhibitors of epsilon - toxin's activity. <P> The specific aims of this Phase I study are: (1) Establish and validate assays for testing the ability of beta -CD derivatives to block the pore formed by C. perfringens epsilon -toxin and to inhibit its cytotoxic activity. (2) Test blocking and inhibitory activity of compounds from a representative library of per-substituted beta -CD derivatives and select the most potent compounds for further development as anti-toxin drugs.<P> Provided that effective inhibitors of epsilon -toxin are found in this feasibility study, in Phase II we will utilize our initial testing data and the crystal structure information available for C. perfringens epsilon -toxin in concert with computational chemistry to design additional beta-CD derivatives with enhanced affinity to the epsilon -toxin pore. The designed compounds will be synthesized and tested in vivo and in vitro with the eventual goal of finding new therapeutics against C. perfringens epsilon -toxin.<P> Epsilon toxin produced by Clostridium perfringens is one of the most lethal bacterial toxins. It is regarded as a potential biological weapon and is included in the list of category B priority agents. Currently, there is no effective treatment for the epsilon -toxin-mediated intoxication; therefore, a great need exists for the development of therapeutics against this biodefense toxin.