| CLINICAL STUDY |
Antidotes to treat Shiga toxin in the gut are in clinical trials, but no compds are on the horizon for treat toxin after it enters the bloodstream, an event that can trigger kidney toxicity & death The researchers are gearing up to produce STARFISH in sufficient quantities to explore the possibility in animal models for "Hamburger disease" |
| MECHANISM OF ACTION |
Shiga toxin is made up of 2 subunits. B which binds to susceptible mammalian cells, allowing A to gain entry & do toxin's dirty work. A strain of E. coli has picked up the gene for Shiga toxin, expressing it as the "hamburger toxin" that's proven deadly in undercooked meat Shiga toxin's B unit is made up of 5 monomers, each having 3 binding sites with varying affinities for cell surface carbohydrates. The pentamer locks onto cells by gripping > 5 carbohydrate ligands simultaneously |
| TECHNOLOGY |
The researchers sought an inhibitor that would mimic this binding approach & latch tenaciously onto the toxin. In designing their molecule, they exploited the crystal structure of the E. coli toxin's B unit complexed to an analog of its carbohydrate receptor. Initially, the team designed a ligand they anticipated might have a high affinity for binding sites 11 angstroem apart on subunit monomers. That ligand consisted of 2 trisaccharide units connected by an 11-angstroem-long tether. But the results were disappointing - "almost useless actually". "Then they came up with the idea of attaching the trisaccharide dimer on each of 5 spokes on core [glucose] in the hopes of 'hitting' 10 binding sites on the 5 monomers". Because of its configuration, the new ligand was dubbed STARFISH Starfish sticks like Velcro to each of the 5 B monomers - but not as expected. Instead of binding to 2 sites/monomer, it binds only to one. Only 5 of Starfish's trisaccharide arms are engaged, leaving the other 5 free to bind another B subunit. The upshot is that Starfish is sandwiched between 2 subunits |
| UPDATE | 02.00 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |