New Compounds Show Promise Against Bioweapon Toxins

Several small molecule candidates have the potential to provide protection against a possible bioterrorism attack using botulinum neurotoxins, according to a new study.

Researchers at the Scripps Research Institute (La Jolla, CA, USA) and the University of Wisconsin (Madison, WI, USA) identified the two compounds and tested their efficacy in both cell-based assays and in mice exposed to the toxin. The two compounds have surprisingly simple molecular structures and are readily amenable to optimization efforts for improvements in their biologic activity. One of the compounds extended survival time of the exposed mice by 36% (from 484 minutes to 659 minutes). Moreover, 16% of the animals treated with the second molecule survived with no obvious symptoms of botulism. The two compounds showed little activity in cellular assays, suggesting that standard cell-based screening methods may miss promising therapeutic candidates. No significant side effects were observed with either molecule.

"These small molecules are the first to show efficacy against this neurotoxin in animal models,” said lead author Kim Janda, Ph.D., a professor of chemistry at the Scripps Research Institute. "Equally important, both have surprisingly simple structures, so their biological activity can be readily optimized. With their different modes of action, they could easily be developed as part of a potent 'cocktail' therapy.”

Botulism is a serious but extremely rare illness. There are seven related botulinum neurotoxins (A through G), although each acts differently and only four attack humans. The toxins kill through paralysis of the respiratory muscles. After attaching themselves to receptors on the neuronal surface--primarily muscle controlling motor neurons activated by acetylcholine--the toxins block the release of acetylcholine proteins, inducing paralysis. One subtype, botulinum neurotoxin A, is a 100 billion times more potent than cyanide and relatively easy to produce, making it a potential biological weapon.


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