Effect of Dendrimer Generation and Aglyconic Linkers on the Binding Properties of Mannosylated Dendrimers Prepared by a Combined Convergent and Onion Peel Approach

Abstract

An efficient study of carbohydrate-protein interactions was achieved using multivalent glycodendrimer library. Different dendrimers with varied peripheral sugar densities and linkers provided an arsenal of potential novel therapeutic agents that could be useful for better specific action and greater binding affinities against their cognate protein receptors. Highly effective click chemistry represents the basic method used for the synthesis of mannosylated dendrimers. To this end, we used propargylated scaffolds of varying sugar densities ranging from 2 to 18 for the attachment of azido mannopyranoside derivatives using copper catalyzed click cycloaddition. Mannopyranosides with short and pegylated aglycones were used to evaluate their effects on the kinetics of binding. The mannosylated dendrons were built using varied scaffolds toward the accelerated and combined “onion peel” strategy These carbohydrates have been designed to fight E. coli urinary infections, by inhibiting the formation of bacterial biofilms, thus neutralizing the adhesion of FimH type 1 lectin present at the tip of their fimbriae against the natural multiantennary oligomannosides of uroplakin 1a receptors expressed on uroepithelial tissues. Preliminary DLS studies of the mannosylated dendrimers to cross- link the leguminous lectin Con A used as a model showed their high potency as candidates to fight the E. coli adhesion and biofilm formation.

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

“…Biochemical analyses of the interaction between FimH LD and α-d-mannose revealed that mannosides with an apolar (hydrophobic) substituent are able to mimic the interactions of high-mannose glycans with the MBD of FimH [82]. For this reason, n-hexyl-and n-heptyl-modified mannosides (i.e., MeMan) have a significant high affinity towards FimH [19,97]. This hydrophobic portion of aglycone interacts with the tyrosine gate through aromatic stacking (non-covalent interaction between aromatic rings) and Van der Waals bonds [77,[97][98][99].…”

“…For this reason, n-hexyl-and n-heptyl-modified mannosides (i.e., MeMan) have a significant high affinity towards FimH [19,97]. This hydrophobic portion of aglycone interacts with the tyrosine gate through aromatic stacking (non-covalent interaction between aromatic rings) and Van der Waals bonds [77,[97][98][99]. Moreover, it was shown that glycomimetics with inhibition constants in the range of 1-20 nM can be obtained by combining the α-anomeric configurations of d-mannose [96,100].…”

“…The polyvalent adhesin inhibitors (carbohydrate dendrimers) were designed to better mimic the interaction of FimH with high-mannose eukaryotic receptors [61]. The affinity, avidity and selectivity of mannosylated glycodendrimers are strengthened throughout by the presence of several mannose residues in the molecule; the so-called "cluster effect" [80,97,104]. Despite their higher affinity with the MBP of FimH, mannosylated glycodendrimers are large-size polar molecules, and these chemical properties reduce their absorption in the gastrointestinal tract, affecting their oral usage [61].…”

Nanomaterials for the Diagnosis and Treatment of Urinary Tract Infections

“…Dendrimers are artificial macromolecules with several functional groups and an intact molecular structure, playing an increasing role in drug delivery via the fabrication of nanoscale particles. Sehad et al [ 159 ] created surface-functionalized dendrimers by attaching mannose sugar on the surface of the dendrimers through copper-catalyzed cyclo-addition click reaction. The mannosylated dendrimers were constructed to examine the impact of mannosylation upon the binding capacity of dendrimers on the bacterial cell surface.…”

Thiol-Ene Click Inspired Late-Stage Modification of Long-Chain Polyurethane Dendrimers

“…First reported by Hawker and Fréchet for the synthesis poly(phenyl benzyl ether) dendrimers, 54 convergent method ensures precise placement of functional groups throughout the dendritic structure that enables the synthesis of functional macromolecules. Though several dendrimers are reported recently employing the convergent method of synthesis, 25,31,[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] there are very few reports on polyurethane dendrimers using this method. 40,[73][74][75]…”