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Scientists design potent anthrax toxin inhibitor

J. Baker, Ph.D., anthrax program officer at NIAID.

Anthrax toxin has three parts: protective antigen (PA), a protein that binds to a receptor on the target cell surface; and two enzymes that must be transported into the cell to cause damage. The enzymatic portions of the toxin enter the cell through a pore created for them by PA after it binds to the cell's outer surface. PA can be seen as a bundle of seven cigar-shaped parts, a molecular arrangement referred to as "polyvalent," meaning it displays multiple binding sites.

The inhibitor designed by Dr. Kane and his colleagues is also polyvalent. Just as a glove matches the shape of a hand more closely than a mitten, and so fits more snugly, the polyvalent inhibitor binds the toxin at multiple sites and is orders of magnitude more potent than an inhibitor that binds at a single site. The multiple peptides on the functionalized liposome are arranged with the same average spacing as the binding sites of the PA molecule, which permits a firmer bond between the two, explains Dr. Kane. When the inhibitor is bound tightly to PA, the subsequent steps of enzyme entry cannot occur and the toxin is effectively neutralized.

The investigators tested the anthrax inhibitor in rats. When given in relatively small doses, injection of the inhibitor at the same time as anthrax toxin prevented five out of nine rats from becoming ill. Slightly higher doses of the inhibitor prevented eight out of nine rats from being sickened by anthrax toxin. Nine additional rats were injected with anthrax toxin only. Of these, eight became gravely ill. This experiment was the first to show the efficacy of a liposome-based polyvalent inhibitor in animals, says Dr. Kane.

Dr. Kane says the recent experiments demonstrate a proof of principle and suggest that polyvalent inhibitors could be used along with antibiotics in a clinical setting. Aside from its inherent toxicity, anthrax toxin also accelerates the disease process.
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Source:NIH/National Institute of Allergy and Infectious Diseases


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