The Experts below are selected from a list of 4860 Experts worldwide ranked by ideXlab platform
Anne Imberty - One of the best experts on this subject based on the ideXlab platform.
-
Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene Glycoconjugates.
Chemistry - A European Journal, 2009Co-Authors: Samy Cecioni, Ruth Lalor, Bertrand Blanchard, Jean-pierre Praly, Anne Imberty, Susan E Matthews, Sébastien VidalAbstract:A family of seven topologically isomeric calix[4]arene Glycoconjugates was prepared through the synthesis of a series of alkyne-derivatised calix[4]arene precursors that are suitable for the attachment of sugar moieties by microwave-assisted copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). The Glycoconjugates thus synthesised comprised one mono-functionalised derivative, two 1,2- or 1,3-divalent regioisomers, one trivalent and three tetravalent topoisomers in the cone, partial cone or 1,3-alternate conformations. The designed Glycoconjugates were evaluated as ligands for the galactose-binding lectin PA-IL from the opportunistic bacterium Pseudomonas aeruginosa, a major causative agent of lung infections in cystic fibrosis patients. Binding affinities were determined by isothermal titration calorimetry (ITC), and the interaction with the lectin was shown to be strongly dependant on both the valence and the topology. Whereas the trivalent conjugate displayed enhanced affinity when compared to a monosaccharide model, the tetravalent conjugates are to-date the highest-affinity ligands measured by ITC. The topologies presenting carbohydrates on both faces of calixarene are the most potent ones with dissociation constants of approximately 200 nM. Molecular modelling suggests that such a multivalent molecule can efficiently chelate two of the binding sites of the tetrameric lectin; this explains the 800-fold increase of affinity achieved by the tetravalent molecule. Surface plasmon resonance (SPR) experiments confirmed that this Glycoconjugate is the strongest inhibitor for binding of PA-IL to galactosylated surfaces for potential applications as an anti-adhesive agent.
-
microbial recognition of human cell surface Glycoconjugates
Current Opinion in Structural Biology, 2008Co-Authors: Anne Imberty, Annabelle VarrotAbstract:Infection by pathogens is generally initiated by the specific recognition of host epithelia surfaces and subsequent adhesion is essential for invasion. In their infection strategy, microorganisms often use sugar-binding proteins, that is lectins and adhesins, to recognize and bind to host Glycoconjugates where sialylated and fucosylated oligosaccharides are the major targets. The lectin/Glycoconjugate interactions are characterized by their high specificity and most of the time by multivalency to generate higher affinity of binding. Recent crystal structures of viral, bacterial, and parasite receptors in complex with human histo-blood group epitopes or sialylated derivatives reveal new folds and novel sugar-binding modes. They illustrate the tight specificity between tissue glycosylation and lectins.
Sébastien Vidal - One of the best experts on this subject based on the ideXlab platform.
-
Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene Glycoconjugates.
Chemistry - A European Journal, 2009Co-Authors: Samy Cecioni, Ruth Lalor, Bertrand Blanchard, Jean-pierre Praly, Anne Imberty, Susan E Matthews, Sébastien VidalAbstract:A family of seven topologically isomeric calix[4]arene Glycoconjugates was prepared through the synthesis of a series of alkyne-derivatised calix[4]arene precursors that are suitable for the attachment of sugar moieties by microwave-assisted copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). The Glycoconjugates thus synthesised comprised one mono-functionalised derivative, two 1,2- or 1,3-divalent regioisomers, one trivalent and three tetravalent topoisomers in the cone, partial cone or 1,3-alternate conformations. The designed Glycoconjugates were evaluated as ligands for the galactose-binding lectin PA-IL from the opportunistic bacterium Pseudomonas aeruginosa, a major causative agent of lung infections in cystic fibrosis patients. Binding affinities were determined by isothermal titration calorimetry (ITC), and the interaction with the lectin was shown to be strongly dependant on both the valence and the topology. Whereas the trivalent conjugate displayed enhanced affinity when compared to a monosaccharide model, the tetravalent conjugates are to-date the highest-affinity ligands measured by ITC. The topologies presenting carbohydrates on both faces of calixarene are the most potent ones with dissociation constants of approximately 200 nM. Molecular modelling suggests that such a multivalent molecule can efficiently chelate two of the binding sites of the tetrameric lectin; this explains the 800-fold increase of affinity achieved by the tetravalent molecule. Surface plasmon resonance (SPR) experiments confirmed that this Glycoconjugate is the strongest inhibitor for binding of PA-IL to galactosylated surfaces for potential applications as an anti-adhesive agent.
Markus W Weishaupt - One of the best experts on this subject based on the ideXlab platform.
-
a semi synthetic oligosaccharide conjugate vaccine candidate confers protection against streptococcus pneumoniae serotype 3 infection
Chemistry & Biology, 2016Co-Authors: Sharavathi Guddehalli Parameswarappa, Katrin Reppe, Andreas Geissner, Petra Menova, Subramanian Govindan, Adam D J Calow, Annette Wahlbrink, Markus W WeishauptAbstract:The identification of immunogenic glycotopes that render Glycoconjugate vaccines protective is key to improving vaccine efficacy. Synthetic oligosaccharides are an attractive alternative to the heterogeneous preparations of purified polysaccharides that most marketed Glycoconjugate vaccines are based on. To investigate the potency of semi-synthetic Glycoconjugates, we chose the least-efficient serotype in the current pneumococcal conjugate vaccine Prevnar 13, Streptococcus pneumoniae serotype 3 (ST3). Glycan arrays containing synthetic ST3 repeating unit oligosaccharides were used to screen a human reference serum for antibodies and to define the recognition site of two ST3-specific protective monoclonal antibodies. The glycan array screens identified a tetrasaccharide that was selected for in-depth immunological evaluation. The tetrasaccharide-CRM197 carrier protein conjugate elicited protective immunity as evidenced by opsonophagocytosis assays and protection against pneumonia caused by ST3 in mice. Formulation of the defined protective lead candidate glycotope has to be further evaluated to elicit optimal long-term immunity.
Paulina Kaplonek - One of the best experts on this subject based on the ideXlab platform.
-
a semisynthetic streptococcus pneumoniae serotype 8 Glycoconjugate vaccine
Science Translational Medicine, 2017Co-Authors: Sharavathi Guddehalli Parameswarappa, Katrin Reppe, Subramanian Govindan, Annette Wahlbrink, Benjamin Schumann, Heung Sik Hahm, Paulina KaplonekAbstract:Glycoconjugate vaccines based on capsular polysaccharides (CPSs) of pathogenic bacteria such as Streptococcus pneumoniae successfully protect from disease but suffer from incomplete coverage, are troublesome to manufacture from isolated CPSs, and lack efficacy against certain serotypes. Defined, synthetic oligosaccharides are an attractive alternative to isolated CPSs but require the identification of immunogenic and protective oligosaccharide antigens. We describe a medicinal chemistry strategy based on a combination of automated glycan assembly (AGA), glycan microarray-based monoclonal antibody (mAb) reverse engineering, and immunological evaluation in vivo to uncover a protective glycan epitope (glycotope) for S. pneumoniae serotype 8 (ST8). All four tetrasaccharide frameshifts of ST8 CPS were prepared by AGA and used in glycan microarray experiments to identify the glycotopes recognized by antibodies against ST8. One tetrasaccharide frameshift that was preferentially recognized by a protective, CPS-directed mAb was conjugated to the carrier protein CRM197. Immunization of mice with this semisynthetic Glycoconjugate followed by generation and characterization of a protective mAb identified protective and nonprotective glycotopes. Immunization of rabbits with semisynthetic ST8 Glycoconjugates containing protective glycotopes induced an antibacterial immune response. Coformulation of ST8 Glycoconjugates with the marketed 13-valent Glycoconjugate vaccine Prevnar 13 yielded a potent 14-valent S. pneumoniae vaccine. Our strategy presents a facile approach to develop efficient semisynthetic Glycoconjugate vaccines.
Pietro Mastroeni - One of the best experts on this subject based on the ideXlab platform.
-
comparative immunogenicity and efficacy of equivalent outer membrane vesicle and Glycoconjugate vaccines against nontyphoidal salmonella
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Francesca Micoli, Renzo Alfini, Francesca Necchi, Simona Rondini, Luisa Lanzilao, Aurel Negrea, Omar Rossi, Cornelia Brandt, Simon Clare, Pietro MastroeniAbstract:Nontyphoidal Salmonellae cause a devastating burden of invasive disease in sub-Saharan Africa with high levels of antimicrobial resistance. Vaccination has potential for a major global health impact, but no licensed vaccine is available. The lack of commercial incentive makes simple, affordable technologies the preferred route for vaccine development. Here we compare equivalent Generalized Modules for Membrane Antigens (GMMA) outer membrane vesicles and O-antigen-CRM 197 Glycoconjugates to deliver lipopolysaccharide O-antigen in bivalent Salmonella Typhimurium and Enteritidis vaccines. Salmonella strains were chosen and tolR deleted to induce GMMA production. O-antigens were extracted from wild-type bacteria and conjugated to CRM 197 . Purified GMMA and Glycoconjugates were characterized and tested in mice for immunogenicity and ability to reduce Salmonella infection. GMMA and Glycoconjugate O-antigen had similar structural characteristics, O-acetylation, and glucosylation levels. Immunization with GMMA induced higher anti–O-antigen IgG than Glycoconjugate administered without Alhydrogel adjuvant. With Alhydrogel, antibody levels were similar. GMMA induced a diverse antibody isotype profile with greater serum bactericidal activity than Glycoconjugate, which induced almost exclusively IgG1. Immunization reduced bacterial colonization of mice subsequently infected with Salmonella . S . Typhimurium numbers were lower in tissues of mice vaccinated with GMMA compared with Glycoconjugate. S. Enteritidis burden in the tissues was similar in mice immunized with either vaccine. With favorable immunogenicity, low cost, and ability to induce functional antibodies and reduce bacterial burden, GMMA offer a promising strategy for the development of a nontyphoidal Salmonella vaccine compared with established Glycoconjugates. GMMA technology is potentially attractive for development of vaccines against other bacteria of global health significance.
-
design of Glycoconjugate vaccines against invasive african salmonella enterica serovar typhimurium
Infection and Immunity, 2015Co-Authors: Simona Rondini, Renzo Alfini, Francesca Micoli, Luisa Lanzilao, Pietro Mastroeni, Massimiliano Gavini, C Brandt, S Clare, Allan SaulAbstract:Nontyphoidal salmonellae, particularly Salmonella enterica serovar Typhimurium, are a major cause of invasive disease in Africa, affecting mainly young children and HIV-infected individuals. Glycoconjugate vaccines provide a safe and reliable strategy against invasive polysaccharide-encapsulated pathogens, and lipopolysaccharide (LPS) is a target of protective immune responses. With the aim of designing an effective vaccine against S. Typhimurium, we have synthesized different Glycoconjugates, by linking O-antigen and core sugars (OAg) of LPS to the nontoxic mutant of diphtheria toxin (CRM197). The OAg-CRM197 conjugates varied in (i) OAg source, with three S. Typhimurium strains used for OAg extraction, producing OAg with differences in structural specificities, (ii) OAg chain length, and (iii) OAg/CRM197 ratio. All Glycoconjugates were compared for immunogenicity and ability to induce serum bactericidal activity in mice. In vivo enhancement of bacterial clearance was assessed for a selected S. Typhimurium Glycoconjugate by challenge with live Salmonella. We found that the largest anti-OAg antibody responses were elicited by (i) vaccines synthesized from OAg with the highest glucosylation levels, (ii) OAg composed of mixed- or medium-molecular-weight populations, and (iii) a lower OAg/CRM197 ratio. In addition, we found that bactericidal activity can be influenced by S. Typhimurium OAg strain, most likely as a result of differences in OAg O-acetylation and glucosylation. Finally, we confirmed that mice immunized with the selected OAg-conjugate were protected against S. Typhimurium colonization of the spleen and liver. In conclusion, our findings indicate that differences in the design of OAg-based Glycoconjugate vaccines against invasive African S. Typhimurium can have profound effects on immunogenicity and therefore optimal vaccine design requires careful consideration.