Botulinum neurotoxins (BoNT) are the etiological agents responsible for botulism, adisease characterized by peripheral neuromuscular blockade and a characteristic flaccidparalysis of humans. With the current warfare and terrorist activities a vastly enhanceddefense against potential bioterrorist weapons is of high priority. BoNTs are potentiallysignificant bioterrorism agents due to their relative ease of production, extreme potencyand duration of paralytic activity. Countermeasures are needed to counteract thepathophysiology of BoNTs. In this context, the development of inhibitors of BoNTs wouldbe a important breakthrough for the control of human botulism, and importantly, futureterrorist threats. To date there are no current interventions that can reverse the effects ofintoxication after the toxin has reached its target inside the cell. As such the overarchinggoal of our proposal is to uncover molecules that can act within an intoxicated cell toprovide symptomatic relief to BoNT/A. There are seven serologically distinct serotypes ofBoNT, however, we will only focused on BoNT/A as it exhibits the most sustainedintoxication and therefore represents the greatest threat of any of the BoNTs. Workingwithin this framework we have taken a two-pronged approach to define such molecules.The first is based on small non-peptidic molecules that can inhibit the intracellular agent,which causes botulinum neurotoxicity, a protease. For this initiative we will preparemechanism-based inhibitors as well as try to enhance the potency of our previous leadcompounds that have confirmed anti-botulinum properties within an animal assay. Oursecond initiative relates to the discovery of molecules that when administered willpromote acetylcholine release and ones that will promote both acetylcholinerelease/acetylcholinesterase inhibition, in other words poly-functional intervention. Ingeneral we know relatively little about truly effective ways to counter toxin action at the'11th hour', and thus total reliance on any particular intervention is likely to be less thansatisfactory. Furthermore, there is a vast difference in the time course of action ofcurrent potential antagonist and the toxin. This poses an enormous challenge in terms ofdiscovery of agents for effective antagonism of BoNT/A poisoning. Against thisbackdrop our research will embrace the discovery of molecules that will provide bothimmediate and possible long-term relief from these neuroparalytic effects of BoNT/A.
Botulinum neurotoxins (BoNT) are the etiological agents responsible for botulism, are the most toxic proteins known to man and are potential bioterrorist weapons. To date there are no current interventions that can reverse the effects of BoNT intoxication once inside the cell. Our goals are to uncover small molecules that can act within an intoxicated cell to provide symptomatic relief to BoNT/A.
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