Grant Boldt

On target.
The inhibitor binds to the business end of BoNT/A in this computer model.

Snapping a Toxin's Back

The neurotoxins produced by the bacteria Clostridium botulinum are the most poisonous substances known: Just 1 gram can kill more than a million people. Long feared as a bioterrorism threat (ScienceNOW, 31 May 2005), the toxins sever communication between nerves and muscles, eventually paralyzing the muscles needed for breathing. Now researchers have found a new way to head off the effects of one of the toxins by preventing it from interrupting this essential connection.

Botulinum toxins are a fickle bunch. In tiny doses, they have become famous as cosmetic injections such as BoTox®, where their paralytic effect smooths facial wrinkles. But they've also been used as biowarfare agents for more than 60 years. Iraq admitted in 1991 to having produced enough concentrated toxin to kill the world's population 3 times over. No comprehensive vaccine exists, and treatment of botulinum exposure relies on antibody therapies that help the body build up a resistance to the toxin. However, such therapies must be started within hours of exposure. "Once these toxins get in the cells, antibody therapy is useless," says Kim Janda, a chemical biologist at the Scripps Institute in San Diego, California.

In an attempt to design a better treatment, Janda and colleagues focused on BoNT/A, the most toxic type of botulinum toxin, and one that has a particularly long life in the body. The group synthesized a number of small molecules and screened them for their ability to counteract the toxin. Based on results from previous studies, they designed the molecules to block the part of the toxin that breaks SNAP-25, a protein in nerve cells essential for nerve-muscle communication. The most promising inhibitor had no trouble entering nerve cells growing on a dish and was able to completely block BoNT/A from snapping SNAP-25.

The inhibitor is the first of its kind shown to work in living cells, says Janda, whose team publishes its findings in an upcoming issue of Chemical Communications. As a result, he says, it would be effective at any time after, or even before, botulinum exposure.

"Compared to the antibody treatment, this is definitely an advance," says Bal Ram Singh, director of the University of Massachusetts Botulinum Research Center in Dartmouth. "They didn't need a special delivery of this material into the cell; it went by itself. That's a good sign," he says. Next, Singh says, the group should try to improve the specificity of the inhibitor so that it only targets nerve cells.

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