Tang found that adefovir fits neatly into a pocket on the surface of edema factor in a way that prevents it from mimicking adenylyl cyclase. In fact, adefovir fits the pocket 10,000 times better than its natural substrate does. Remarkably, adefovir's affinity for edema factor is four times greater than its attraction to the hepatitis B virus enzyme it was designed to inhibit.
Because the drug is such a precise match to its target, it may require only small amounts of adefovir to effectively block edema factor. Such small amounts should produce few, if any, side effects in short-term use for anthrax.
How much difference adefovir might make in treating inhalational anthrax in humans is still untested. Although anthrax makes two toxins, they work together. Mice infected with a strain of anthrax that makes only lethal factor and not edema factor are 100 times more likely to survive.
"The two toxins and protective antigen all multiply each other's effects," explains Tang, "so blocking any one of them should have a major impact."
Other research teams are working on drugs that interfere with protective antigen or lethal factor but none is looking at drugs that have already been through safety testing or have been used clinically.
"This is a classic example of serendipity in science," said Paula Flicker, Ph.D., a biophysicist at the National Institute of General Medical Sciences (NIGMS), which partially supported the research. "Curiosity-driven studies of important enzyme unexpectedly led directly to possible treatments for anthrax."
This work also points out "the importance of supporting a cadre of basic researchers," added Flicker, "who can quickly apply their expertise to national medical emergencies."
Tang's studies suggest that adefovir may also inhibit similar toxins produced by more common disease-causing bacteria including: Bordetella per
Contact: John Easton
University of Chicago Medical Center