Wei-Jen Tang, Ph.D., Associate Professor in the Ben May Institute for Cancer Research, and his team have discovered that a drug approved by the FDA for treatment of chronic hepatitis B is actually more effective in blocking one of two anthrax toxins. Bacillus anthracis, the bacterium that causes anthrax, functions by producing two deadly toxins that work in tandem, edema factor and lethal factor. The drug, adefovir dipivoxil, works by blocking the effects of edema factor. Their findings were published in the March 2, 2004 issue of the Proceedings of the National Academy of Sciences.

“These toxins pack a one-two punch that makes inhalational anthrax extremely harmful,” says Tang. “For the first time, we have a clinically approved drug that, at least in tissue culture, completely eradicates half of that toxic team, and does it at non-toxic doses.”

In the early stages of infection, edema factor interferes with the host’s immune response, allowing the bacteria to spread and multiply. Later, edema factor causes massive tissue damage, including the release of fluid into the lungs and blackened necrotic lesions.

Tang’s discovery occurred as part of a process, beginning with a paper published in Nature in which he described the three-dimensional structure of edema factor and showed how it works by hijacking a normal cellular process and forcing it into overdrive. The paper was published in January 2002, just after the terrorist attacks involving anthrax that occurred in the fall of 2001, and for that reason, his paper received national attention. A researcher at Gilead Sciences who worked with the drug saw the article and felt that perhaps adefovir would affect this toxin in the same way as it inhibited the hepatitis B virus. He contacted Tang and sent him samples which Tang then used in conjunction with the Advanced Photon Source at Argonne National Laboratory. There, he and his team were able to study how the drug bound to its target, which in turn revealed how it neutralized edema factor.

Their work revealed that the drug is a precise match to its target, and may require only a small dose to effectively block edema factor. Since the anthrax bacteria works through a combination of two toxins and a protective antigen, blocking one of those elements should have a major impact on future treatment. In fact, adefovir’s affinity for edema factor is four times greater than its attraction to the hepatitis B virus enzyme it was designed to inhibit. The effectiveness in treating inhalational anthrax in humans is still untested, but mice infected with a strain of anthrax producing only lethal factor and not edema are 100 times more likely to survive. “We all hope that the bioterror attacks of 2001 never recur,” says Tang, “but if something happens, it would be nice to have better treatment options.”

Tang has continued his anthrax research through a collaboration with Professor Milan Mrksich and colleagues in the Department of Chemistry, hoping to identify inhibitors of anthrax lethal factor. The initial findings from this work are very promising and will appear soon in Nature Biotechnology.

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DISCOVERIES
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FOREFRONT
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