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Chemical Neutralizes Anthrax Toxin

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10:49am, October 3, 2001
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Scientists have created a synthetic compound that disables the toxin that makes the bacterial disease anthrax so lethal. Meanwhile, another research team has discovered a gene that protects some mice against anthrax. These findings could lead to an antidote to the anthrax toxin and help clarify the mechanism by which it kills.

Whether the new compound can serve as an antitoxin in people remains unclear since the scientists have tested it only in rats, says R. John Collier of Harvard Medical School in Boston. Nevertheless, the concept of neutralizing anthrax toxin has appeal because the current treatments, which target the bacterium, and the vaccine now in use have drawbacks.

When a person inhales spores of Bacillus anthracis–the microbe that causes anthrax–they unleash three proteins that combine to form a toxin. This triad makes blood pressure plummet, causes hemorrhaging, and can lead to coma and death.

The proteins attack human cells as a team. One protein–protective antigen (PA)–binds to a receptor on the cell surface and is cleaved by enzymes there. The part of PA that remains stuck, called PA63, provides a docking site for the other anthrax proteins–lethal factor and edema factor. Once assembled, the toxin enables lethal factor to enter the cell. There, it chops up proteins, setting into motion the chain of events that leads to anthrax's symptoms, says Nicholas C. Duesbery of the Van Andel Research Institute in Grand Rapids, Mich.

Since no drug in use at present disables the toxin, Collier and his colleagues set out to create such a compound. First, they identified a peptide, or partial protein, that bonds to PA63 in lab tests. Next, they linked together multiple copies of the peptide. In test tubes, this synthetic molecule, which they call polyvalent inhibitor (PVI), prevented the natural anthrax proteins from binding to PA63.

When injected into rats, PVI protected the animals against subsequent exposure to 10 times the normally lethal dose of anthrax toxin, the researchers report in the October Nature Biotechnology. Without PVI treatment, rats died within hours.

Antibiotics can kill B. anthracis but have no effect on the toxin already present in the body when symptoms appear, says Robert C. Liddington of the Burnham Institute in La Jolla, Calif. The vaccine poses problems, too. It can cause side effects, and "it's hard to justify vaccinating a whole country against one particular agent of biological terrorism," he says.

Ideally, a toxin antidote would be mass-produced and kept in storage around the country, Collier says.

Researchers are currently charting the anthrax proteins' course in the body. In the Oct. 2

Current Biology, William F. Dietrich of the Howard Hughes Medical Institute and Harvard Medical School in Boston and his colleagues report that certain variations of a gene called Kif1C, which encodes a protein that ushers other proteins around inside cells, protect mice from the effects of the anthrax toxin.

"We've got the PA63 molecular activity on one end and the disease on the other end. The Kif1C gene gives us some clues as to where to look in between," Duesbery says.

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