SYNTHESIS OF NEXT-GENERATION INHIBITORS OF BOTULINUM NEUROTOXIN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Botulinum neurotoxin (BoNT), a protein that is produced by Clostridium botulinum, is the most poisonous protein in the world. The active site of BoNT includes a zinc endopeptidase, whose structure has been elucidated by x-ray crystallography. Herein we propose to synthesize a library of inhibitors for the zinc endopeptidase subunit. The key structural element of these inhibitors is a 2- or 3-aryl indole. These moieties will be synthesized using oxidative coupling technology that has recently been developed in the PI's laboratory. Biological testing of the inhibitors will be performed in the laboratory of a collaborator at the Botulism Research Center at the University of Massachusetts-Dartmouth.