Studies Point Way to New Anthrax Therapies. Part 2

In one new study, John Young of the University of Wisconsin-Madison and colleagues at Harvard University say they’ve identified the precise portal through which anthrax toxins enter macrophages. The key is a protein called anthrax toxin receptor (ATR), which binds with PA.

“For more than a decade now the scientific community has been wondering what is the identify of this receptor,” says Young.

The work is based on earlier experiments aimed at finding clues to how viruses reproduce and how certain cells had become resistant to viral infection. The researchers saw that cells without ATR became resistant to anthrax toxin. Returning ATR restored their susceptibility to the poison.

Young’s group then engineered a key snippet of ATR, which they mixed with rodent cells and anthrax toxin. They found the cells were totally protected from the poison, which had bound harmlessly to the receptor fragments.

“The protective antigen now is soaked up by a sponge, which mops up the toxin and prevents it from attaching to cell surfaces,” says Young. However, he says the receptor fragment has been tested only on cells in a plastic lab dish and not yet in any animals.

Young’s group also found that ATR appears to be related to another gene and its protein, called TEM8, which is elevated in patients with colorectal cancer.

The second report, by Robert Liddington of the Burnham Institute in La Jolla, Calif., gives scientists a close-up view of the structure of LF, the enzyme that gives anthrax part of its punch.

Using a scanning technique called X-ray crystallography, Liddington and his colleagues mapped LF and saw that it binds with a group of molecules called mitogen-activated protein kinase kinase (MAPKK). LF splits these MAPKK compounds, which are important in cell signaling, and fatally disrupts healthy cell communication.

At the core of LF’s virulence is a deep gulf into which MAPKK can nestle, and a lone zinc atom that ultimately triggers the cleaving. “If we could stop the action of this toxin, then we could save some lives,” Liddington says.

R. John Collier, a Harvard University anthrax expert, says his lab has been working on a number of potential therapies to neutralize PA, LF and EF that might work in tandem with antibiotics. Two approaches, including a “dominant negative inhibitor,” disrupt the PA syringe and keep it from injecting the two other toxins into target cells.

Collier says Harvard is “in active negotiations” with drug companies to develop these therapies commercially.

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