The synthesis of a multivalent heterobifunctional ligand for specific interaction with Shiga toxin 2 produced by E. coli O157:H7

The Crystal Structure of Shiga Toxin Type 2 with Bound Disaccharide Guides the Design of a Heterobifunctional Toxin Inhibitor

“…In particular, Asp-16 of Stx1 is "locked" in the observed conformation through its interactions with Specific Heterobifunctional Ligand That Sequesters Stx2a-The crystal structure data showing the orientation of disaccharide 2 in site 2 of Stx2a suggest that a heterobifunctional ligand similar to the BAIT-P k molecule used to engage Stx1 with HuSAP (30) should also be a viable proposition for binding and neutralization of Stx2a. We synthesized the target compound PolyBAIT-P k NAc 3, in which 2-acetamido-2-deoxy-␣-D-galactose replaced the terminal ␣-Gal of P k trisaccharide (35). It consists of three distinct features essential for supramolecular complex formation (Fig.…”

“…The heterobifunctional ligand designed to bind Stx2 selectively coined PolyBAIT-P k NAc 3 (35) incorporates the P k NAc trisaccharide to which is fused a 1,2-O-pyruvate acetal. When this entity is attached to a polymeric scaffold, the multivalent heterobifunctional ligand forms a supramolecular complex where the radially symmetric HuSAP acts as a template protein that sequesters Stx2a.…”

Enterohemorrhagic Escherichia coli and a Fresh View on Shiga Toxin-Binding Glycosphingolipids of Primary Human Kidney and Colon Epithelial Cells and Their Toxin Susceptibility

“…Progress in understanding the protein-carbohydrate dependent pathogen-host interaction is the basis for the manufacture of novel glycotherapeutics basically postulated by the pioneers of glycoscience more than two decades ago [373,374]. Carbohydratebased multivalent inhibitors have already been created in the early phase of glycoresearch and in the following years with a few showing the potential to competitively inhibit the binding of Stx to glycosides with Gb3-core and to neutralize its cytotoxic activity in vitro [320,327,328,[375][376][377][378][379]. Real-time interaction analysis of GSLs in model membranes and membrane preparations with lectins of all kinds, including Stxs and viral hemagglutinins, employing the recently applied surface acoustic wave (SAW) technology [170,380,381] combined with inhibition assays using, e.g., multivalent glycan derivatives, has a promising perspective for the development of anti-adhesion therapeutics.…”

Recent Advances in Engineering Polyvalent Biological Interactions

“…Jacobson et al synthesized potent Shiga toxin inhibitors. 63 They found that a P k trisaccharide containing a terminal 2-acetamido-2-deoxy-α- d -galactopyranosyl residue instead of the terminal α- d -galactopyranosyl residue displayed preferential binding to the more dangerous Stx2 Shiga toxin (compared to the Stx1 counterpart). The elimination of toxin activity was through supramolecular complex formation between the trisaccharide inhibitor, Stx2 and Human serum amyloid P.…”