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Stanford University

Wednesday, 30 June 2004

Anthrax Toxin - Working Towards an Antidote

Thiang Yian Wong, Robert Schwarzenbacher and Robert C. Liddington
The Burnham Institute, 10901 North Torrey Pines Rd, La Jolla, CA

Anthrax makes a deadly cocktail of three toxin proteins that flood the bloodstream, leading to rapid death if the infection is not diagnosed and treated in its early stages. Even antibiotic treatments can fail when the Anthrax bacterium, Bacillus anthracis, has already produced lethal levels of toxins. The poisonous protein called Lethal Factor (LF) rapidly blocks signals to recruit immune cells to fight the infection. Another enzyme Edema Factor (EF) causes the release of fluid into the lungs and is deadly on its own. Protective Antigen (PA) facilitates the entry of these toxin proteins across the cell membrane, and into target cells, through its complex pore-forming channel.

LF is the greatest source of damage in highly fatal cases of inhalation anthrax. An anti-toxin that stops LF would be a vital addition to combined therapy with existing treatments (antibiotics, anti-PA antibodies, critical care). Scientists from The Burnham Institute in La Jolla, California, together with colleagues at the Harvard Medical School and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) have taken a big step forward in developing a drug to inhibit the LF toxin. The group screened small molecules from the National Cancer Institute Diversity Set to identify chemical compounds that can block LF. They made crystals of LF bound to these candidate inhibitors and used SSRL facility to analyze the interactions of these compounds with LF. The research concluded that the most effective inhibitors targeted the active center via hydrophobic interactions and also deprived LF of zinc. The scientists are now working on chemically generating even better inhibitors.