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Madison, WI, United States

Grant
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase II | Award Amount: 745.47K | Year: 1998

This proposal describes strategies to synthesize potent inhibitors of botulinum neurotoxin metalloproteases. These metalloproteases [BoTx protease] have been shown to be the molecular effectors of the paralytic effects of these toxins. Mechanism-based drug design will be applied to develop peptide-derived inhibitors of these proteases. At the same time, experiments to develop non-peptide templates for creating orally active or injectable inhibitors of these proteases will begin, based on use of combinatorial chemistry on known orally active inhibitors of metalloproteases. During Phase, I we will characterize inhibitor activity with a set of 10 15 lead compounds using a procedure based on incubation of various toxin proteolytic substrates with clostridial neurotoxins. These substrates are cleaved by the toxin metalloprotease generating fragments with an electrophoretic mobility different from those of the uncleaved substrates. These compounds are expected to function as pharmacological antagonists and to serve as important probes useful for neurobiological research as adjuncts for reversing effects of BoTx in treating achalasia and related disorders in humans, and as important lead compounds in antitoxin drug development. The product of our work from our biological screen will be provided to investigators at USAMRICD and USANRID for evaluation. These botulinum inhibitors have potential as antidotes under battle field 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. Additionally there is potential to use these inhibitors for toxin detection and as novel cell biology research tools.


Grant
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 99.16K | Year: 1998

This proposal describes strategies to develop a neural cell specific delivery vehicle system which utilizes the target specificity of the botulinum toxin family to provide a generic platform for the delivery of drugs to the neuronal cytosol. Using a multi-disciplinary approach, we will construct and evaluate a non-toxic form of botulinum neurotoxin (BoNT) for use as a neural cell specific delivery vehicle. In Phase I, we will set out to accomplish: 1) Construct of BoNT-derived delivery vehicles coupled to a reporter molecule. 2) Evaluate the delivery capabilities of the BoNT-derived vehicles. 3). Determine the minimal components of BoNT for successful drug delivery. In Phase II, we will: synthesize aminoquinoline derivatives that can be coupled to the delivery vehicle and increase the number of BoNT delivery vehicle delivery drug binding sites. The work proposed here is intended to lead to systems which will function as important pharmacological delivery systems in antitoxin therapy and possibly serve in targeting therapeutic agents to nerve terminals for a variety of disease states. BENEFITS: These drug delivery vehicles have potential as antitoxin therapeutics under battle field conditions. They also would benefit consumer food safety as well as create new applications in medical therapeutics for the treatment of various neurological disorders. The dual use applications of this technology are economically significant.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 90.80K | Year: 1998

N/A


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 299.33K | Year: 1997

CURRENT LUMINESCENCE BIOASSAYS RELY SOLELY UPON MESUREMENT OF LUMINESCENCE INTENSITY TO GENERATE INFORMATION. MULTIPLE COLORS FROM BEETLE LUCIFERASE HAS CREATED THE OPPORTUNITY TO INCREASE ASSAY INFORMATION CONTENT BY USING MULTIPLEXING TECHNIQUES TO MEASURE LIGHT INTENSITIES AT DIFFERENT WAVELENGTHS. THIS PROVIDES GREATER ASSAY RELIABILITY, PRECISION, AND ABILITY TO MEASURE CONCURRENT MOLECULAR EVENTS. THE EXCELLENT PERFORMANCE OF BEETLE LUCIFERASE ENZYMES IN BIOASSAY METHODS YIELDS THE HIGHEST QUANUM EFFICIENCY OF ANY LUMINESCENCE METHODOLOGY, AND DEMONSTRATES SUPERIOR PRECISION, LINEARITY, AND RAPIDITY. TO FURTHER ASSESS THE FEASIBILITY OF USING MULTIPLEXING TO INCRASE THE COMMERCIAL POTENTIAL OF BIOLUMINESCENCE ASSAYS, RESEARCHERS ARE IDENTIFYING NOVEL SUBSTITUTIONS THAT REGULATE COLOR BY EXAMINING THE RELATIONSHIP BETWEEN AMINO ACID SUBSTITUTIONS IN THE PRIMARY STRUCTURES OF BETLE LUCIFERASES TO THE ENZYMES' SPECTRAL PROPERTISE.


Grant
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 99.89K | Year: 1997

This proposal describes strategies to synthesize potent inhibitors of botulinum neurotoxin metalloproteases. These metalloproteases [BoTx protease] have been shown to be the molecular effectors of the paralytic effects of these toxins. Mechanism-based drug design will be applied to develop peptide-derived inhibitors of these proteases. At the same time, experiments to develop non-peptide templates for creating orally active or injectable inhibitors of these proteases will begin, based on use of combinatorial chemistry on known orally active inhibitors of metalloproteases. During Phase, I we will characterize inhibitor activity with a set of 10 15 lead compounds using a procedure based on incubation of various toxin proteolytic substrates with clostridial neurotoxins. These substrates are cleaved by the toxin metalloprotease generating fragments with an electrophoretic mobility different from those of the uncleaved substrates. These compounds are expected to function as pharmacological antagonists and to serve as important probes useful for neurobiological research as adjuncts for reversing effects of BoTx in treating achalasia and related disorders in humans, and as important lead compounds in antitoxin drug development. The product of our work from our biological screen will be provided to investigators at USAMRICD and USANRID for evaluation. These botulinum inhibitors have potential as antidotes under battle field 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. Additionally there is potential to use these inhibitors for toxin detection and as novel cell biology research tools.

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