Avant-Propos

En présentant un dossier de contributions rédigées autour de l’histoire économique de l’Espagne et de la France au cours des XIXe et XXe siècles dans le cadre d’un hommage à Gérard Chastagnaret, la présente livraison de Rives méditerranéennes revêt un caractère particulier. Au moment de son départ à la retraite, la revue se devait de lui souligner son attachement et de lui adresser ses remerciements, et ce pour plusieurs raisons. La première et la plus directe est évidente : Rives méditerrané..

Multivalent glycoconjugates as anti-pathogenic agents

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 strategie

Multivalent glycoconjugates as anti-pathogenic agents

Peer reviewe

Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers

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International audienc

Développement de méthodes chimiosélectives pour la conjugaison de peptides

GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Multivalent scaffolds in glycoscience: an overview

International audienc

Cyclopeptide scaffolds in carbohydrate-based synthetic vaccines

International audienc

Conception et synthèse de nouveaux glycoclusters biologiquement actifs

Les interactions multivalentes sucre/protéine sont impliquées dans de nombreux processus biologiques tels que l'adhésion hôte-pathogène, la communication cellulaire ou les réponses immunitaires. La conception de glycoconjugués capables de présenter des motifs osidiques en cluster est essentielle, non seulement pour étudier ces phénomènes de reconnaissance complexes mais aussi pour développer des agents biologiquement actifs. Dans ce contexte, l'objectif de ma thèse a été de synthétiser de nouveaux glycoclusters et d'évaluer leurs propriétés biologiques. Ces glycoclusters ont été obtenus en conjuguant des sucres sur des cyclopeptides par des méthodes chimiosélectives (cycloaddition de Huisgen et ligation oxime). Des composés tetravalents, hexavalents et hexadécavalents d'architectures et de compositions variables ont été synthétisés, entièrement caractérisés puis évalués au laboratoire ou dans le cadre de collaborations avec différentes cibles. Un glycocluster hexadécavalent fucosylé a ainsi pu être identifié comme puissant inhibiteur de l'interaction de la lectine PA-IIL de la bactérie Pseudomonas aeruginosa à une concentration subnanomolaire. Une autre famille de composés associant des sucres et des peptides a montré des propriétés immunologiques uniques, notamment pour activer les cellules NK contre des cellules cancéreuses sans déclencher de phénomène d'autoapoptose. Mots clés : chimie des sucres, chimie des peptides, glycoclusters, ligations chimiosélectives, interactions sucre-protéine, lectine, cellule NK.Multivalent carbohydrates-protein interactions are involved in a large variety of biological processes such as host-pathogen adhesions, cell communication or immune responses. The design of glycoconjugates displaying multiple copies of sugars as cluster is essential, not only to study these complex recognition processes but also to develop bioactive agents. In this context, the objective of my PhD was to synthesize new glycoclusters and evaluate their biological properties. These glycoclusters were obtained by conjugating carbohydrate moieties and peptides using chemoselective ligations (Huisgen cycloaddition and oxime ligation). Tetravalent, hexavalent and hexadecavalent glycoclusters with variable structures and compositions were synthesized, fully characterized and biologically evaluated with different targets in our laboratory or in collaborations. A hexadecavalent fucosylated glycocluster was thus identified as a strong inhibitor of the lectin PA-IIL from Pseudomonas aeruginosa at subnanomolar concentration. Another type of molecule containing carbohydrate and peptides has showed unique immunological properties, in particular for the activation of NK cells against tumors without inducing apoptotic effect Key words: carbohydrate chemistry, peptide chemistry, chimioselective ligations, glycoclusters, carbohydrate-protein interactions, lectin, NK cell.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF