High Affinity Glycodendrimers for the Lectin LecB from Pseudomonas aeruginosa.

Following an iterative oxime ligation procedure, cyclopeptide (R) and lysine-based dendron (D) were combined in all possible arrangements and successively functionalized with $\alpha$-fucose and $\beta$-fucose to provide a new series of hexadecavalent glycosylated scaffolds (i.e., scaffolds RD16, RR16, DR16, and DD16). These compds. and smaller analogs (tetra- and hexavalent scaffolds R4 and R6) were used to evaluate the influence of the ligand valency and architecture, and of the anomer configuration in the binding to the $\alpha$Fuc-specific lectin LecB from Pseudomonas aeruginosa. Competitive enzyme-linked lectin assays (ELLA) revealed that only the RD16 architecture displaying $\alpha$Fuc reaches strong binding improvement (IC50 of 0.6 nM) over $\alpha$MeFuc, and increases the $\alpha$-selectivity of LecB. Dissocn. const. of 28 nM was measured by isothermal titrn. microcalorimetry (ITC), which represents the highest affinity ligand ever reported for LecB. ITC and mol. modeling suggested that the high affinity obsd. might be due to an aggregative chelate binding involving four sugar head groups and two lectins. Interestingly, unprecedented binding effects were obsd. with $\beta$-fucosylated conjugates, albeit being less active than the corresponding ligands of the $\alpha$Fuc series. In particular, the more flexible lysine-based dendritic structures showed a slight inhibitory enhancement in comparison with those having cyclopeptide core. [on SciFinder(R)]


Soumis le 12 avril 2018