Journal
MOLECULAR PHARMACEUTICS
Volume 9, Issue 3, Pages 394-403Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp200490b
Keywords
E. coli; antiadhesin; mannopyranoside; glycodendrimer; triazole; lysine
Funding
- Ministere du Developpement Economique, Innovation et Exportation (MDEIE) du Quebec
- NSERC Canada
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Uropathogenic Escherichia coli infections, ultimately leading to cystitis and pyelonephritis, are initially mediated by the adhesion of the bacterial FimH to the transmembrane glycoprotein uroplakin-1a present at the surface of urothelial cells. The adhesion is based on the recognition and high avidity binding between the high-mannose glycans of the uroplakin and the FimH, a man nose-specific lectin located at the tip of type 1 fimbriae. We found that synthetic multiantennary mannopyranosides glycodendrons, harboring triazole functionality at the anomeric position, were potent hemagglutination inhibitors of guinea pig erythrocytes and E. coli. A mannosylated dendrimer exposing up to sixteen sugar residues showed an HAI titer of 1 mu M and was thus 500-fold more potent than the corresponding monovalent methyl alpha-D-mannopyranoside. The synthesis of the glycodendrons involved highly efficient solid-phase synthesis of branched L-lysine scaffolds, diazo transfer reaction on the terminal amine residues, and 1,3-dipolar copper-catalyzed azide-alkyne cycloaddition using propargyl alpha-D-mannopyranoside.
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