Posted on 10/08/2001 1:30:57 AM PDT by jennyp
A possible breakthrough in development of an effective antrax anti-toxin just happened to be announced in the October 2001 issue of Nature Biotechnology.
Combating anthrax
Anthrax is a deadly disease that could potentially be used in biological terrorism or warfare. The bacterium that causes anthrax produces a toxin that is extremely deadly, causing a disease that is invariably fatal if not treated immediately with antibiotics. Now, a group of researchers led by John Collier and George Whitesides may have come up with a means of combating the toxin. They have designed a polyvalent inhibitor (PVI) of the toxin that protects rats for at least one week after receiving doses of toxin 10-times the minimum lethal amount. Rats exposed to the toxin in the absence of PVI normally survive for only a few hours.
Using their knowledge that the anthrax bacterium secretes three nontoxic proteins that assemble into toxin complexes on mammalian cell membranes, Collier and his team screened peptide libraries for an inhibitor that prevents the toxin assembly process. Their screen identified a 12-amino acid peptide that inhibited assembly, albeit weakly. They then set about creating a PVI by covalently linking multiple copies of this inhibitor to a flexible polyacrylamide backbone, increasing the inhibitory activity of the peptide by about 7,500-fold.
Their method of developing synthetic, polymeric, polyvalent inhibitors of protein-protein interactions may also turn out to be a useful tool for increasing the therapeutic potency of drugs such as antitumor peptides, growth factor receptor agonists, or molecules with related mechanisms of action.
The Abstract (free registration req'd)October 2001 Volume 19 Number 10 pp 958 - 961
Designing a polyvalent inhibitor of anthrax toxin
Michael Mourez1, Ravi S. Kane2, Jeremy Mogridge1, Steve Metallo2, Pascal Deschatelets2, Bret R. Sellman1, George M. Whitesides2 & R. John Collier1
1. Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.
2. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138.
Correspondence should be addressed to R J Collier. e-mail: jcollier@hms.harvard.edu
Screening peptide libraries is a proven strategy for identifying inhibitors of proteinligand interactions. Compounds identified in these screens often bind to their targets with low affinities. When the target protein is present at a high density on the surface of cells or other biological surfaces, it is sometimes possible to increase the biological activity of a weakly binding ligand by presenting multiple copies of it on the same molecule. We isolated a peptide from a phage display library that binds weakly to the heptameric cell-binding subunit of anthrax toxin and prevents the interaction between cell-binding and enzymatic moieties. A molecule consisting of multiple copies of this nonnatural peptide, covalently linked to a flexible backbone, prevented assembly of the toxin complex in vitro and blocked toxin action in an animal model. This result demonstrates that proteinprotein interactions can be inhibited by a synthetic, polymeric, polyvalent inhibitor in vivo.
You die from the toxin, not the anthrax. If we can beat the toxin, as well as take down the anthrax bacteria it becomes a far less pressing threat.
This is very good news, even if it's just working in mice. That's a significant step towards working in humans.
If they really pushed it, how soon do you think they could do a test on humans, and also how soon could they ramp up production assuming it works in humans?
Yes, this explains why you tend to die if you don't get on antibiotics until you start showing symptoms. By that time, even if all the bacteria were killed immediately, they've been busy producing the toxin, which is still there in the bloodstream doing its dirty work.
I am no expert on the production of oligopeptides, but I imagine a few of the biotech comapnies in CA and Boston could get their collective acts together in short order.
Your timing was good since I just heard on the radio that a second case of anthrax was confirmed in one of the co-workers of the index case in Boca (they both worked at the national tabloid The Sun.
Hmmm. Well, maybe we could get the terrorists to hold off on using up their inventory for a while. :-)
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