Synthesis and structure–activity relationships of di- and trisaccharide inhibitors for Shiga-like toxin Type 1

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Abstract
The syntheses of galabiose and Pk-trisaccharide analogues in which selected hydroxy groups are replaced by O-methyl, amino deoxy, acetamido deoxy, and carboxyalkyl groups are reported. The ability of these inhibitors to block E. coli verotoxin 1 binding to its mammalian cell-surface receptor are evaluated by a solid-phase competition assay. The synthesis of a biotinylated glycoconjugate for this assay is described, wherein a Pk-trisaccharide tether derivative 70 is constructed and covalently attached to bovine serum albumin followed by biotinylation. Galabiose derivatives 4 and 5 that contain a carboxymethyl or carboxyethyl substituent at O-2 of the β-galactose residue show 15–20-fold activity gains over the methyl glycoside of galabiose. This enhanced activity is not observed for the corresponding carboxymethyl-substituted Pk-trisaccharide analogue 13. The inhibition data are rationalized with the solved crystal structure for verotoxin 1 complexed with a Pk-trisaccharide analogue and provide insight for the design of dimeric inhibitors that can exploit the unique binding-site distribution of the toxin’s B subunit. This discussion provides a further example of the important role played by ordered water molecules in sugar–protein complexes.

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