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Small Molecule Inhibitors of C. Perfringens Epsilon-Toxin

Investigators
Karginov, Vladimir
Institutions
Innovative Biologics, Inc
Start date
2007
End date
2008
Objective
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.

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.

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.

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.

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.

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.

Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project number
1R43AI074105-01
Categories
Clostridium
Natural Toxins
Bacterial Pathogens