Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i>
The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of <i>Helicobacter pylori</i> 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 ho...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/18/4281 |
| _version_ | 1797553295030484992 |
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| author | Mark Reihill Lorenzo Guazzelli Han Remaut Stefan Oscarson |
| author_facet | Mark Reihill Lorenzo Guazzelli Han Remaut Stefan Oscarson |
| author_sort | Mark Reihill |
| collection | DOAJ |
| description | The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of <i>Helicobacter pylori</i> 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 <i>N</i>-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. |
| first_indexed | 2024-03-10T16:13:19Z |
| format | Article |
| id | doaj.art-23544ef2e9a24d23ad76ca324ba03fc4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:13:19Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-23544ef2e9a24d23ad76ca324ba03fc42023-11-20T14:13:00ZengMDPI AGMolecules1420-30492020-09-012518428110.3390/molecules25184281Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i>Mark Reihill0Lorenzo Guazzelli1Han Remaut2Stefan Oscarson3Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, IrelandDepartment of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, ItalyVIB-VUB Center for Structural Biology, Pleinlaan 2, Building E, 1050 Brussel, BelgiumCentre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, IrelandThe syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of <i>Helicobacter pylori</i> 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 <i>N</i>-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.https://www.mdpi.com/1420-3049/25/18/4281<i>H. pylori</i>Lewis bfucosesuicide inhibitorsBabAlectins |
| spellingShingle | Mark Reihill Lorenzo Guazzelli Han Remaut Stefan Oscarson Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> Molecules <i>H. pylori</i> Lewis b fucose suicide inhibitors BabA lectins |
| title | Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> |
| title_full | Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> |
| title_fullStr | Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> |
| title_full_unstemmed | Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> |
| title_short | Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of <i>Helicobacter pylori</i> |
| title_sort | synthesis of fucose derivatives with thiol motifs towards suicide inhibition of i helicobacter pylori i |
| topic | <i>H. pylori</i> Lewis b fucose suicide inhibitors BabA lectins |
| url | https://www.mdpi.com/1420-3049/25/18/4281 |
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