Multivalent calix[4]arene-based mannosylated dendrons as new FimH ligands and inhibitors

FimH is a mannose-specific adhesin that mediates the adhesion of uropathogenic Escherichia coli (UPEC) to urothelial cells and can be targeted thanks to the glycoside cluster effect given by carbohydrate-lectin interactions [1]. Among the different synthetic scaffolds used to build multivalent glycoconjugates [2], calixarenes show peculiar properties dependent on the different valences of the scaffold and on the stereochemical disposition of the saccharide units. Thus, we inserted two trivalent mannosylated dendrons onto the upper rim of a calix[4]arene scaffold, obtaining hexavalent glycocalixarenes (Figure 1). The antiadhesive properties of compounds 5a-b was then assessed by an assay based on yeast cell agglutination to UPEC, a highly conserved FimH-dependent binding property among isolated E. coli strains. On-cell STD NMR experiments, acquired in the presence of UPEC living cells, confirmed the specific binding of calixarenes functionalized with Man units (5a-b) to FimH proteins at the cell surface [3]. Mannosylated calixarenes 5a-b are thus promising hit compounds for the development of novel antiadhesive therapies aimed at fighting urinary tract infections caused by UPEC. [1] S. N. Abraham, D. Sun, J. B. Dale, E. H. Beachey, Nature 1988, 336, 682 – 684 [2] A. Palmioli, P. Sperandeo, S. Bertuzzi, A. Polissi, C. Airoldi, Bioorg. Chem. 2021, 112 [3] A. Palmioli, L. Moretti, C. A. Vezzoni, L. Legnani, P. Sperandeo, L. Baldini, F. Sansone, C. Airoldi, A. Casnati, Bioorg. Chem. 2023, 138