Combinatorial Transition State Analog Inhibitor Library for Botulinum Toxin

Botulism is a debilitating and often fatal intoxication for which there is no approved pharmacological treatment. The intent of Phase I research is threefold. First, to demonstrate that a combinatorial strategy can be used to identify novel, peptide-based inhibitors of BoNT/A light chain activity. Second, to decode and resynthesize the best inhibitors of this library. Third, to confirm the activity of these leads in `in vitro assays' at USAMRCD. This work will generate significant structure-activity data for in vivo activity optimization in Phase II. Screening of these secondary libraries will provide data which can be utilized in combination with molecular modeling studies to refine our knowledge of the active site geometry and eventually to design non-peptide organic molecule libraries for SAR refinement. Eventually these libraries will produce leads which will be developed into therapeutic agents. The lack of an effective pharmacological treatment for botulinum intoxication assures a ready.market for an effective and selective antagonist. Such a drug would be of great importance for both civilian and military populations intoxicated by battlefield exposure, contaminated food or while receiving BoNT therapy for muscle disorders.