Anthrax toxin, secreted by the anthrax bacterium, is made of proteins and toxic enzymes that bind together to inflict damage on a host organism. Rather than targeting the anthrax bacterium or toxin – the approach taken by the majority of current therapies – the new inhibitor blocks the receptors where anthrax toxin attaches in the body. And because the nanoscale assembly of molecules is designed to bind to multiple sites on the host receptor, it is naturally more potent.
The new approach led to a 50,000-fold increase in potency in cell culture, and the inhibitor protected rats from anthrax toxin in the study. The general concept also could be applied to designing inhibitors for other pathogens, including SARS, influenza, and AIDS, the researchers note.
The inhibitor designed by the Rensselaer-Toronto team is “polyvalent,” which means that it displays multiple copies of receptor-binding peptides, allowing it to bind at multiple sites and become more potent than an inhibitor that binds to a single site. For the current experiment, the researchers made four different polyvalent inhibitors and then tested each in cell culture. They found that the most potent of the four inhibitors enabled more than a 50,000-fold enhancement in activity compared to an inhibitor that was not based on polyvalency.
This potent inhibitor was then characterized more fully and tested in rats. Five out of six rats injected only with anthrax toxin died; all six rats injected with toxin and a non-polyvalent inhibitor died. But the new polyvalent inhibitor protected all six rats in the experiment, with no signs of adverse side effects.
Once fully developed, administering the new inhibitor to patients could help reduce the high mortality rates associated with inhalational anthrax, according to the researchers. Antibiotics slow the progression of infection by targeting the anthrax bacterium, but they do not counter the advanced destructive effects of anthrax toxin in the body. Inhalation anthrax still has a fatality rate of 75 percent even after antibiotics are given, according to the Centers for Disease Control and Prevention. “Combining the inhibitor with antibiotic therapy may increase the likelihood of survival for an infected person,” Kane said.
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