| RESEARCH |
The carbohydrate ligand has two trisaccharide units at the tips of five tethers that radiate from a central glucose core. The decavalent inhibitor binds to multiple binding sites on the toxin--preventing the toxin from attaching itself to carbohydrates on cell surfaces, its usual mechanism of action. The in vitro potency of the multivalent inhibitor was 10 million times higher than that of the corresponding monovalent ligand-toxin interaction--suggesting that it could point the way toward development of a potent antitoxin. Currently, there is no effective treatment for Shiga-like toxin once it enters the bloodstream. The ligand designed initially by AUTHOR's group complexes with only one site (site 2) of Shiga-like toxin's three binding sites, but the researchers have since investigated the possibility of creating a ligand capable of also binding to site 1, the site with the next highest affinity. "We have some preliminary data on a second-generation inhibitor that suggests that a design that places an oligosaccharide in site 1 as well as site 2 yields even more active inhibitors," AUTHOR says. "We have recently completed a preliminary investigation into the scale-up of our synthesis of the molecule to the multigram level, with a view to conducting animal trials,". "At the same time, we have investigated modified designs for the molecule and find that several changes preserve activity while simplifying the synthesis. We are in discussions to either form a start-up biotechnology company or license this invention, which we find has several other potentially attractive applications." |
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