C. perfringens epsilon-toxin (ETX) is a potential biological weapon included in the list of category B priority agents. The overall goal of this proposal is to identify and perform in vivo testing of new inhibitors of ETX 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. Results from our SBIR Phase I project demonstrated that beta-cyclodextrin derivatives designed to block the transmembrane channel formed by epsilon-toxin can inhibit its cytotoxicity at low micromolar concentrations. Based on the successful completion of this feasibility study, we propose to design, synthesize and screen a library of beta-cyclodextrin derivatives for inhibitors of epsilon-toxin's activity and test selected lead compounds in mice.
The specific aims of this Phase II study are: (1) Optimize the assay for testing the ability of beta-cyclodextrin derivatives to inhibit the cytotoxic activity of C. perfringens epsilon-toxin. (2) Utilize initial testing data in concert with pharmaceutical chemistry to design and synthesize a biased library of beta- cyclodextrin derivatives with an enhanced affinity to the epsilon-toxin pore. (3) Screen the library using the cell-based assay to select the most potent inhibitors and test their ability to block the pore formed by ETX. (4) Perform toxicity, pharmacokinetic and efficacy tests in mice challenged with epsilon-toxin using at least three compounds to select in vivo validated leads. In the long-term, subsequent pre-clinical and clinical studies will lead to the development of a new drug 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 5-toxin-mediated intoxication; therefore, a great need exists for the development of therapeutics against this biodefense toxin. ? ? ?
| Robinson, Tanisha M; Jicsinszky, Laszlo; Karginov, Andrei V et al. (2017) Inhibition of Clostridium perfringens epsilon toxin by ?-cyclodextrin derivatives. Int J Pharm 531:714-717 |
| Karginov, Vladimir A (2013) Cyclodextrin derivatives as anti-infectives. Curr Opin Pharmacol 13:717-25 |
| Nestorovich, Ekaterina M; Karginov, Vladimir A; Bezrukov, Sergey M (2010) Polymer partitioning and ion selectivity suggest asymmetrical shape for the membrane pore formed by epsilon toxin. Biophys J 99:782-9 |
