| 1. |
- Andre, Sabine, et al.
(författare)
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Glycocluster Design for Improved Avidity and Selectivity in Blocking Human Lectin/Plant Toxin Binding to Glycoproteins and Cells
- 2010
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 7:6, s. 2270-2279
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Tidskriftsartikel (refereegranskat)abstract
- Blocking lectin/toxin binding to human cells by suitable inhibitors can therapeutically protect them from harmful effects. Clustered design of ligand presentation holds the promise of affinity increase relative to the free sugar and inherent selectivity among lectin targets. Using first a solid-phase assay with a glycoprotein presenting N-glycans as lectin-reactive probe, we assessed the inhibitory potency of bi- to tetravalent clusters on a plant toxin and three human adhesion/growth-regulatory lectins. Enhanced avidity relative to the free sugar was detected together with lectin-type selectivity. These effects were confirmed on the level of cells in vitro, also for two leguminous lectins. The lack of toxicity in cell proliferation assays excluded concerns to further work on these compounds. The given cluster design and the strategic combination of the two assay systems of increasing biorelevance will thus be helpful to take the next steps in drug development, e.g. tailoring the sugar headgroup.
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| 2. |
- Bernardi, Anna, et al.
(författare)
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Multivalent glycoconjugates as anti-pathogenic agents
- 2013
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Ingår i: Chemical Society Reviews. - : Royal Society of Chemistry (RSC). - 0306-0012 .- 1460-4744. ; 42:11, s. 4709-4727
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Forskningsöversikt (refereegranskat)abstract
- Multivalency plays a major role in biological processes and particularly in the relationship between pathogenic microorganisms and their host that involves protein-glycan recognition. These interactions occur during the first steps of infection, for specific recognition between host and bacteria, but also at different stages of the immune response. The search for high-affinity ligands for studying such interactions involves the combination of carbohydrate head groups with different scaffolds and linkers generating multivalent glycocompounds with controlled spatial and topology parameters. By interfering with pathogen adhesion, such glycocompounds including glycopolymers, glycoclusters, glycodendrimers and glyconanoparticles have the potential to improve or replace antibiotic treatments that are now subverted by resistance. Multivalent glycoconjugates have also been used for stimulating the innate and adaptive immune systems, for example with carbohydrate-based vaccines. Bacteria present on their surfaces natural multivalent glycoconjugates such as lipopolysaccharides and S-layers that can also be exploited or targeted in anti-infectious strategies.
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| 3. |
- Fourniere, Viviane, et al.
(författare)
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Synthesis of the Lewis b pentasaccharide and a HSA-conjugate thereof
- 2010
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 66:39, s. 7850-7855
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori, a gastric pathogen, binds to various blood group antigens, including the Lewis types, present in the gastric tissue and a relation between the presentation of the ligands and the overall strength of binding has been assumed. Synthetic Lewis b tetra- and hexasaccharide conjugates are available but not the analogous pentasaccharide. An efficient synthesis of the amino spacer equipped Lewis b pentasaccharide, 3-aminopropyl alpha-L-fucopyranosyl-(1 -> 2)-beta-D-galactopyranosyl-(1 3)-[alpha-L-fucopyranosyl-(1 -> 4)]-2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1 -> 3)-beta-D-galactopyranoside, is presented to enable further investigation of the carbohydrate recognition process of H. pylori.
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| 4. |
- Houser, Josef, et al.
(författare)
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A Soluble Fucose-Specific Lectin from Aspergillus fumigatus Conidia - Structure, Specificity and Possible Role in Fungal Pathogenicity
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Aspergillus fumigatus is an important allergen and opportunistic pathogen. Similarly to many other pathogens, it is able to produce lectins that may be involved in the host-pathogen interaction. We focused on the lectin AFL, which was prepared in recombinant form and characterized. Its binding properties were studied using hemagglutination and glycan array analysis. We determined the specificity of the lectin towards l-fucose and fucosylated oligosaccharides, including alpha 1-6 linked core-fucose, which is an important marker for cancerogenesis. Other biologically relevant saccharides such as sialic acid, d-mannose or d-galactose were not bound. Blood group epitopes of the ABH and Lewis systems were recognized, Le(Y) being the preferred ligand among others. To provide a correlation between the observed functional characteristics and structural basis, AFL was crystallized in a complex with methyl-alpha,L-selenofucoside and its structure was solved using the SAD method. Six binding sites, each with different compositions, were identified per monomer and significant differences from the homologous AAL lectin were found. Structure-derived peptides were utilized to prepare anti-AFL polyclonal antibodies, which suggested the presence of AFL on the Aspergillus' conidia, confirming its expression in vivo. Stimulation of human bronchial cells by AFL led to IL-8 production in a dose-dependent manner. AFL thus probably contributes to the inflammatory response observed upon the exposure of a patient to A. fumigatus. The combination of affinity to human epithelial epitopes, production by conidia and pro-inflammatory activity is remarkable and shows that AFL might be an important virulence factor involved in an early stage of A. fumigatus infection.
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| 5. |
- Lahmann, Martina, et al.
(författare)
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Transformations of chromanol and tocopherol and synthesis of ascorbate conjugates
- 2011
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 67:9, s. 1654-1664
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Tidskriftsartikel (refereegranskat)abstract
- alpha-Tocopherol and as a model compound pentamethylchromanol could be transferred into simple and more complex 5a-ether derivatives including galactopyranose as well as ascorbic acid conjugates. Following elaboration of a glucopyranoside spacer element this could be used for tethering the vitamin E and the vitamin C components to give novel conjugates for subsequent biostudies concerning their proposed synergism of antioxidant properties in tissues.
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| 6. |
- Safari, Dodi, et al.
(författare)
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Gold nanoparticles as carriers for a synthetic Streptococcus pneumoniae type 14 conjugate vaccine
- 2012
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Ingår i: Nanomedicine. - : Future Medicine Ltd. - 1743-5889 .- 1748-6963. ; 7:5, s. 651-662
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Coupling of capsular polysaccharides of pathogens to immunogenic protein carriers (conjugate vaccines) improves carbohydrate immune response. Our idea is to explore gold nanoclusters as carriers to prepare fully synthetic carbohydrate vaccines. Materials & methods: Gold glyconanoparticles bearing a synthetic tetrasaccharide epitope related to the Streptococcus pneumoniae type 14 capsular polysaccharide (Pn14PS), the T-helper ovalbumin 323-339 peptide (OVA(323-339)), and D-glucose were prepared by a one-pot method. Their immunogenicity was tested in mice. Cytokine levels after spleen cell stimulation with OVA(323-339) were analyzed using a luminex-multiplex cytokine assay. The capacity of the evoked antibodies to promote the uptake of S. pneumoniae type 14 by leukocytes was assessed. Results & discussion: Glyconanoparticles containing 45% of tetrasaccharide and 5% OVA(323-339) triggered specific anti-Pn14PS IgG antibodies. Cytokine levels confirmed that glyconanoparticles led to T-helper cell activation. The antisaccharide antibodies promoted the phagocytosis of type 14 bacteria by human leukocytes, indicating the functionality of the antibodies. Conclusion: Gold nanoparticles have great potential as carriers for the development of a great diversity of fully synthetic carbohydrate-based vaccines.
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| 7. |
- Shan, Yulong, et al.
(författare)
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Lactosamine from lactulose via the Heyns rearrangement : a practical protocol
- 2013
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Ingår i: Tetrahedron Letters. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0040-4039 .- 1359-8562. ; 54:30, s. 3960-3961
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Tidskriftsartikel (refereegranskat)abstract
- The Heyns rearrangement is possibly one of the oldest, easiest and most economic ways to synthesise 2-deoxy-2-amino sugars. Initially reported yields were disappointingly low, but in the late 90s Wrodnigg and Stutz discovered modified reaction conditions that gave substantially increased yields, making the reaction viable on preparative scale. Requiring larger amounts of N-acetyl lactosamine, we utilised the reported reaction conditions and found that additional modifications, especially in the work-up procedure-for example employing rapid filtration of crude diethyl ether precipitates, were necessary to make this approach robust in the research laboratory environment.
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| 8. |
- Sulak, Ondrej, et al.
(författare)
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A TNF-like Trimeric Lectin Domain from Burkholdeda cenocepacia with Specificity for Fucosylated Human Histo-Blood Group Antigens
- 2010
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Ingår i: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 18:1, s. 59-72
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Tidskriftsartikel (refereegranskat)abstract
- The opportunistic pathogen Burkholderia cenocepacia expresses several soluble lectins, among them BC2L-C. This lectin exhibits two domains: a C-terminal domain with high sequence similarity to the recently described calcium-dependent mannose-binding lectin BC2L-A, and an N-terminal domain of 156 amino acids without similarity to any known protein. The recombinant N-terminal BC2L-C domain is a new lectin with specificity for fucosylated human histo-blood group epitopes H-type 1, Lewis b, and Lewis Y, as determined by glycan array and isothermal titration calorimetry. Methylselenofucoside was used as ligand to solve the crystal structure of the N-terminal BC2L-C domain. Additional molecular modeling studies rationalized the preference for Lewis epitopes. The structure reveals a trimeric jellyroll arrangement with striking similarity to TNF-like proteins, and to BcIA, the spore protein from Bacillus anthracis which may play an important role in bioadhesion of anthrax spores in human lungs.
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| 9. |
- Sundgren, Andreas, et al.
(författare)
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Synthesis of 6-PEtN-alpha-D-GalpNAc-(1 -> 6)-beta-D-Galp-( 1 -> 4)-beta-D-GlcpNAc-(1 -> 3)-beta-D-Galp-(1 -> 4)-beta-D-Glcp, a Haemophilus influenzae lipopolysacharide structure, and biotin and protein conjugates thereof
- 2010
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Ingår i: Beilstein Journal of Organic Chemistry. - : Beilstein Institut. - 2195-951X .- 1860-5397. ; 6, s. 704-708
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Tidskriftsartikel (refereegranskat)abstract
- Background: In bacteria with truncated lipopolysaccharide structures, i.e., lacking the O-antigen polysaccharide part, core structures are exposed to the immune system upon infection and thus their use as carbohydrate surface antigens in glycoconjugate vaccines can be considered and investigated. One such suggested structure from Haemophilus influenzae LPS is the phosphorylated pentasaccharide 6-PEtN-alpha-D-GalpNAc-(1 -> 6)-beta-D-Galp-(1 -> 4)-beta-D-GlcpNAc-(1 -> 3)-beta-D-Galp-(1 -> 4)-beta-D-Glcp. Results: Starting from a spacer-containing lactose derivative a suitably protected lacto-N-neotetraose tetrasaccharide structure was constructed through subsequential couplings with two thioglycoside donors, a glucosamine residue followed by a galactose derivative, using NIS/AgOTf as promoter. Removal of a silyl protecting group at the primary position of the non-reducing end residue afforded an acceptor to which the terminal a-galactosamine moiety was introduced using a 2-azido bromo sugar and halide assisted coupling conditions. Global deprotection afforded the non-phosphorylated target pentasaccharide, whereas removal of a silyl group from the primary position of the non-reducing end residue produced a free hydroxy group which was phosphorylated using H-phosphonate chemistry to yield the phosphoethanolamine-containing protected pentasaccharide. Partial deprotection afforded the phosphorylated target pentasaccharide with a free spacer amino group but with a protected phosphoethanolamino group. Conjugation of the spacer amino group to biotin or dimethyl squarate followed by deprotection of the phosphoethanolamino group and, in the case of the squarate derivative, further reaction with a protein then afforded the title conjugates. Conclusion: An effective synthesis of a biologically interesting pentasaccharide structure has been accomplished. The target pentasaccharide, an alpha-GalNAc substituted lacto-N-neotetraose structure, comprises a phosphoethanolamine motif and a spacer aglycon. Through the spacer, biotin and protein conjugates of the title compound have been constructed to allow further use in biological experiments.
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| 10. |
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