A recently described bangle lectin (PHL) from the bacterium Photorhabdus asymbiotica was identified as a mainly fucose-binding protein that could play an important role in the host-pathogen interaction and in the modulation of host immune response. Structural studies showed that PHL is a homo-dimer that contains up to seven L-fucose-specific binding sites per monomer. For these reasons, potential ligands of the PHL lectin: α-L-fucopyranosyl-containing mono-, di-, tetra-, hexa- and dodecavalent ligands were tested. Two types of polyvalent structures were investigated - calix[4]arenes and dendrimers. The shared feature of all these structures was a C-glycosidic bond instead of the more common but physiologically unstable O-glycosidic bond. The inhibition potential of the tested structures was assessed using different techniques - hemagglutination, surface plasmon resonance, isothermal titration calorimetry, and cell cross-linking. All the ligands proved to be better than free L-fucose. The most active hexavalent dendrimer exhibited affinity three orders of magnitude higher than that of standard L-fucose. To determine the binding mode of some ligands, crystal complex PHL/fucosides 2 - 4 were prepared and studied using X-ray crystallography. The electron density in complexes proved the presence of the compounds in 6 out of 7 fucose-binding sites.
- MeSH
- antibakteriální látky chemie farmakologie terapeutické užití MeSH
- bakteriální infekce farmakoterapie mikrobiologie MeSH
- bakteriální proteiny antagonisté a inhibitory chemie izolace a purifikace metabolismus MeSH
- dendrimery chemie farmakologie terapeutické užití MeSH
- erytrocyty MeSH
- fukosa analogy a deriváty farmakologie terapeutické užití MeSH
- hemaglutinace účinky léků MeSH
- interakce hostitele a patogenu účinky léků MeSH
- krystalografie rentgenová MeSH
- lektiny antagonisté a inhibitory chemie izolace a purifikace metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- Photorhabdus metabolismus MeSH
- povrchová plasmonová rezonance MeSH
- rekombinantní proteiny chemie izolace a purifikace metabolismus MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The C-type lectin DC-SIGN expressed on immature dendritic cells is a promising target for antiviral drug development. Previously, we have demonstrated that mono- and divalent C-glycosides based on d-manno and l-fuco configurations are promising DC-SIGN ligands. Here, we described the convergent synthesis of C-glycoside dendrimers decorated with 4, 6, 9, and 12 α-l-fucopyranosyl units and with 9 and 12 α-d-mannopyranosyl units. Their affinity against DC-SIGN was assessed by surface plasmon resonance (SPR) assays. For comparison, parent O-glycosidic dendrimers were synthesized and tested, as well. A clear increase of both affinity and multivalency effect was observed for C-glycomimetics of both types (mannose and fucose). However, when dodecavalent C-glycosidic dendrimers were compared, there was no difference in affinity regarding the sugar unit (l-fuco, IC50 17 μM; d-manno, IC50 12 μM). For the rest of glycodendrimers with l-fucose or d-mannose attached by the O- or C-glycosidic linkage, C-glycosidic dendrimers were significantly more active. These results show that in addition to the expected physiological stability, the biological activity of C-glycoside mimetics is higher in comparison to the corresponding O-glycosides and therefore these glycomimetic multivalent systems represent potentially promising candidates for targeting DC-SIGN.
- MeSH
- biomimetické materiály chemie farmakologie MeSH
- fukosa chemie MeSH
- inhibiční koncentrace 50 MeSH
- lektiny typu C antagonisté a inhibitory MeSH
- mannosa chemie MeSH
- molekuly buněčné adheze antagonisté a inhibitory MeSH
- receptory buněčného povrchu antagonisté a inhibitory MeSH
- Publikační typ
- časopisecké články MeSH
The discovery of effective ligands for DC-SIGN receptor is one of the most challenging concepts of antiviral drug design due to the importance of this C-type lectin in infection processes. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides but glycosidic linkages are accessible to both chemical and enzymatic degradations. To avoid this problem, the synthesis of stable glycoside mimetics has attracted increasing attention. In this work we establish for the first time mono- and divalent C-glycosides based on d-manno and l-fuco configurations as prospective DC-SIGN ligands. In particular, the l-fucose glycomimetics were more active than the respective d-mannose ones. The highest affinity was assessed for simple 1,4-bis(α-l-fucopyranosyl)butane (SPR: IC50 0.43 mM) that displayed about twice higher activity than natural ligand Le(x). Our results make C-glycosides attractive candidates for multivalent presentations.
- MeSH
- biomimetika MeSH
- fukosa chemie MeSH
- glykosidy chemická syntéza chemie MeSH
- lektiny typu C chemie metabolismus MeSH
- lidé MeSH
- mannosa chemie MeSH
- molekulární struktura MeSH
- molekuly buněčné adheze chemie metabolismus MeSH
- receptory buněčného povrchu chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
