Abstract
The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of Helicobacter pylori are reported. Blood group Antigen Binding Adhesin (BabA), a bacterial membrane-bound lectin, binds to human ABO and Lewis b blood group structures displayed on the surface of host epithelial cells. Crystal structures of the carbohydrate-recognition domain revealed a conserved disulfide bonded loop that anchors a critical fucose residue in these blood group structures. Disruption of this loop by N-acetylcysteine results in reduced BabA-mediated adherence to human gastric tissue sections and attenuated virulence in Lewis b-expressing transgenic mice. With a view of creating specific inhibitors of the lectin, we designed and successfully synthesised six fucose-derived compounds with thiol motifs to engage in a thiol-disulfide exchange with this disulfide bond of BabA and form a glycan-lectin disulfide linkage. Branching and extending the fucose backbone with 2- and 3-carbon thiol motifs delivered a range of candidates to be tested for biological activity against BabA.
Highlights
IntroductionHelicobacter pylori, a Gram-negative helical-shaped bacterium, infects the stomach of almost 50%
Helicobacter pylori, a Gram-negative helical-shaped bacterium, infects the stomach of almost 50%of the population [1,2,3]
With a view of creating specific inhibitors of the lectin, we designed and successfully synthesised six fucose-derived compounds with thiol motifs to engage in a thiol-disulfide exchange with this disulfide bond of Blood group Antigen Binding Adhesin (BabA) and form a glycan-lectin disulfide linkage
Summary
Helicobacter pylori, a Gram-negative helical-shaped bacterium, infects the stomach of almost 50%. Cys189-Cys197 disulfide bond, providing optimism for this and neutrophil infiltration when their drinking water was dosed with NAC. BabA carbohydrate binding site, high doses of NAC are required to reduce the CL2 disulfide and. Targets 1 and 2 both exhibited axial thiol motifs from the 2-position, with the structures being branched to attempt to maintain H-bonding interactions with the 2-OH. Inspired by the work of Cleator et al, we envisioned proceeding via oxidation of the 2-position followed by addition of an alkenyl Grignard reagent (Scheme 2) [22]. This would provide us with a handle to perform thiolene reactions to introduce thiol groups.
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