Newswise — The Institute of Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook has been awarded a $1.4 million grant by the Defense Threat Reduction Agency of the Department of Defense to develop an antidote to botulism, a rare but potentially fatal disease that could potentially be used in biowarfare.
The exploratory grant award, which can be expanded to a larger project grant, is for two years and is the first research consortium grant that ICB&DD has received in partnership with Brookhaven National Laboratory (BNL).
"This is a critical area for biodefense and public health," said Samuel L. Stanley, Jr., MD, President of Stony Brook University. "I am pleased that Stony Brook scientists and their collaborators have created a multidisciplinary team to develop a new therapy for these neurotoxins."
The ICB&DD team for the research project on Botulinum Neurotoxin Inhibitors consists of Drs. Subramanyan Swaminathan at BNL, Department of Biology; Iwao Ojima, Distinguished Professor and Director of the ICBⅅ Peter Tonge, Department of Chemistry; and Robert Rizzo, Department of Applied Mathematics and Statistics.
"This is a very interesting and promising multidisciplinary research project,” said Dr. Ojima. “These cross-boundary collaborations are essential for the future success in biomedical sciences and science as a whole."
The project is entitled “Structure-Based Discovery of Pan-Active Botulinum Neurotoxin Inhibitors.” Clostridium botulinum neurotoxins (BoNTs), the toxins that cause botulism, are the most potent toxins known to humans and are considered to be potential biowarfare agents. As a consequence, these neurotoxins are classified as Category A priority pathogens by the federal Centers for Disease Control and Prevention. Currently, the only treatment for botulism is antibody based, which is not be effective once the toxin enters the cell. Thus, there is a compelling need to develop novel chemotherapeutics against these neurotoxins.
Dr. Swaminathan, who has been working with Botulinum Neurotoxins for many years, said that one of the project goals is to develop a single drug that is effective against different strains, or serotypes, of botulism. This drug discovery project includes structure determination of enzyme-inhibitor complexes; virtual screening to identify small molecules, transition state analogs or peptidomimetics of substrate peptides that can be accommodated in the active site of multiple serotypes; synthesis of novel compounds and further modifications required for a broad spectrum of BoNTs; and enzymology and SAR for additional compound design.
Dr. Tonge said that, as with any drug discovery effort, the goals are to develop a drug that has a high affinity for the target in order to reduce the amount of the drug that is needed, and that is also very specific to that target to reduce the possibility of side effects.
"This is a project that neither Stony Brook nor Brookhaven Lab could have pursued on their own," said Dr. John (Jack) H. Marburger, III, Vice President for Research at Stony Brook University. "It's a perfect match between BNL's expertise in substances important for homeland security, and Stony Brook's expertise in molecular level chemistry and advanced computing. I can't think of a better team to make a breakthrough on our long-standing vulnerability to this deadly toxin than the ICB&DD."
The ICB&DD was established in 2004 with a goal of becoming a world-class center of excellence in chemical biology and drug discovery at Stony Brook University. The rapid and significant advancements in chemical biology during the last decade have clearly demonstrated that solutions for a vast majority of medical problems rely on the understanding of the molecular basis of diseases, therapeutic targets, drug actions, and drug resistance. ICB&DD promotes highly productive interdisciplinary and collaborative research among chemists, biologists, medicinal chemists, pharmacologists, and physicians to attack major biomedical problems to find solutions including the discovery of novel therapeutic drugs.
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