The Design and Synthsis of Orally Active Inhibitors of Botulinum Toxin Metalloproteases

Period of Performance: 03/02/1998 - 03/02/2000

$746K

Phase 2 SBIR

Recipient Firm

Promega Corporation
2800 Woods Hollow Road
Madison, WI 53711
Principal Investigator

Research Topics

Abstract

This Phase II proposal is designed to continue a unique interdisciplinary research involving a team that has at its disposal all skills and talents to design, synthesize and test novel organic structures that inhibit all or several of the known BoNT-metalloproteases. Innovations in combinatorial chemistry applied to structural leads discovered in Phase I will form the rationale for developing tight-binding inhibitors of BoNT-metalloproteases. New methods for high through-put screening of potential inhibitors based on construction of fusion proteins and application of Promega technology are described. X-ray crystallography of both native BoNT light chains and BoNT-proteases complexed with transition state analog inhibitors will provide structural information that will facilitate the optimization of inhibitors. BENEFITS: These botulinum inhibitors have potential as antidotes under battlefield conditions as well as to detoxify military equipment and environments that have been exposed to the toxin. They also would benefit consumer food safety as well as create new applications in medical therapeutics for the treatment of muscular disorders. The dual use applications of this technology are economically significant.