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Scientists Step Closer to Blocking
Anthrax Toxin
By Heather
Rock Woods and Irimpan Mathews
Scientists working on SSRL’s
macromolecular crystallography beam lines have taken a big step forward
in developing a drug to stop the most deadly of the toxins secreted by
Anthrax.
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An x-ray crystal structure
of an inhibitor (NSC 12155)
bound in the active site of the Lethal Factor protein.
(Image courtesy of Robert Liddington) |
Anthrax makes a lethal 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 bottom line is we need anti-toxin
approaches to treating Anthrax in the late stages,” said faculty
researcher Robert Liddington of The Burnham Institute in La Jolla,
California. “Antibiotics kill the bacteria but are only effective if
given early because they don’t take out the toxins.” Liddington’s group
published two papers in the June 2 issue of Nature Structural &
Molecular Biology, together with colleagues at the Harvard Medical
School and the United States Army Medical Research Institute of
Infectious Diseases (USAMRIID).
The poisonous protein called Lethal Factor
(LF) is the greatest source of damage in highly fatal cases of
inhalation anthrax. LF swiftly blocks signals that 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) protein acts as a transporter system, enabling LF and EF to
enter target cells.
An anti-toxin that stops LF would be a
vital addition to combined therapy with existing treatments
(antibiotics, anti-PA antibodies, critical care).
“The other alternative is vaccination,
which is used by the armed forces. However, the side effects are
significant enough that it’s unlikely you would want to vaccinate the
whole population,” Liddington said.
The Burnham group screened small molecules
from the National Cancer Institute Diversity Set to identify chemical
compounds that can block LF.
“This was step one, to make inhibitors
that work in a cell-based assay,” Liddington said. “In other words, the
cells don’t die when exposed to LF bound with an inhibitor in a lab
setting.”
Then the researchers began working on
chemically generating even better inhibitors. Part of the process
involves shining SSRL’s x-rays on LF-inhibitor co-crystals to find their
atomic-resolution structure. They also collected data at the National
Synchrotron Light Source in New York.
“The structure is key because it tells how
and where the drug binds with atomic precision, which allows us to
determine ways to alter the drug molecules to bind more strongly and
more specifically to LF,” he said.
The final phase would be to take the
effective anti-toxin, “stockpile it and hope it never needs to be used,”
Liddington said.
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