Publications (45)195.72 Total impact
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Article: Thiyl Glycosylation of Propargylated Octasilsesquioxane: Synthesis and Lectin-Binding Properties of Densely Glycosylated Clusters on a Cubic Platform
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ABSTRACT: a][] Samuele Staderini, [a] Nathalie Berthet, [b] Pascal Dumy, [b][] Olivier Renaudet, [b] and Alessandro Dondoni* [a] Keywords: Carbohydrates / Cluster compounds / Glycoconjugates / Click chemistry / Radical reactions / Alkynes / Photochemistry A new polyhedral oligomeric silsesquioxane (POSS) deriva-tive with a periphery of eight PEGylated chains function-alized with terminal propargyl groups was synthesized start-ing from commercially available octavinyl-POSS. The photo-induced free-radical coupling of this octapropargyl POSS de-rivative with various sugar thiols enabled the preparation of globular hexadecavalent glycoclusters. Thus, it appears that according to the alkyne hydrothiolation mechanism, two thiyl radicals were added across each triple bond of the POSS scaffold side-chains. The affinities of some of the densely glycosylated clusters towards certain lectins were measured by the Enzyme-Linked Lectin Assay (ELLA). The binding selectivity of Concanavalin A between the hexadecavalentEuropean Journal of Organic Chemistry 01/2013; · 3.33 Impact Factor -
Article: Multivalent glyco(cyclo)peptides.
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ABSTRACT: Because of the importance of carbohydrate-protein interactions in biological processes, the development of glycoclusters and glycodendrimers capable of mimicking the multivalent display of carbohydrates at the cell surface has become a major field of research over the last decade. Among the large variety of scaffolds that are now available, peptides and cyclopeptides are widely used for the multivalent presentation of glycans. This review will provide an overview of the most recent advances in the preparation and utilization of linear glycopeptides and glycocyclopeptides in glycobiology.Chemical Society Reviews 12/2012; · 28.76 Impact Factor -
Article: Glycoside and peptide clustering around the octasilsesquioxane scaffold via photoinduced free-radical thiol-ene coupling. The observation of a striking glycoside cluster effect.
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ABSTRACT: Two series of multivalent octasilsesquioxane glyco- and peptido-conjugates were synthesized using the photoinduced free-radical thiol-ene coupling (TEC). The first series was obtained by coupling C-glycosylpropyl thiols and cysteine containing peptides with the known octavinyl octasilsesquioxane while the second series was obtained by reacting glycosyl thiols with a new octasilsesquioxane derivative displaying eight PEGylated chains functionalized with terminal allyl groups. The evaluation of the binding properties of mannoside and glucoside clusters toward Concanavalin A by Enzyme-Linked Lectin Assay (ELLA) revealed a modest glycoside cluster effect. On the other hand, the PEGylated POSS-based glycocluster featuring eight N-acetyl-glucosamine residues showed high affinity toward Wheat Germ Agglutinin to give a measured IC(50) at 3 nM. The calculated relative potency per number of sugar unit (rp/n) was superior to a value of 10(6), thus revealing the occurrence of a striking glycoside cluster effect.Organic & Biomolecular Chemistry 03/2012; 10(16):3269-77. · 3.70 Impact Factor -
Article: Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations.
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ABSTRACT: Synthetic heteroglycoclusters are being subjected to increasing interest due to their potential to serve as selective ligands for carbohydrate-binding proteins. In this paper, we describe an expedient strategy to prepare cyclopeptides displaying well-defined distributions and combinations of carbohydrates. By using both oxime ligation and copper(I)-catalyzed alkyne-azide cycloaddition, two series of compounds bearing binary combinations of αMan, αFuc or βLac in an overall tetravalent presentation, and either 2:2 or 3:1 relative proportions, have been prepared.Beilstein Journal of Organic Chemistry 01/2012; 8:421-7. · 2.52 Impact Factor -
Article: Synthesis of Glycocyclopeptides by Click Chemistry and Inhibition Assays with Lectins
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ABSTRACT: A new series of tetravalent glycocyclopeptides has been prepared using the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). When compared with our oximation procedure previously described, we found that the CuAAC strategy led to glycoclusters with similar yield and purity. In addition, the binding properties of these two series of glycoclusters (i.e., with oxime or triazole linkage) were studied with several lectins. Interestingly, while no difference of binding was observed with the mannose-specific lectin from Canavalia ensiformis (ConA), the compound displaying αFuc through oxime linkage has revealed a significant binding improvement with the fucose-specific lectin from Ulex europaeus (UEA-I).Journal of Carbohydrate Chemistry 09/2011; 30(7-9):458-468. · 0.63 Impact Factor -
Article: Access to biomolecular assemblies through one-pot triple orthogonal chemoselective ligations.
Angewandte Chemie International Edition 02/2011; 50(8):1901-4. · 13.45 Impact Factor -
Article: Cyclic neoglycodecapeptides: how to increase their inhibitory activity and selectivity on lectin/toxin binding to a glycoprotein and cells.
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ABSTRACT: Protein (lectin/toxin)-glycan interaction can be clinically harmful so that the design of inhibitors has become an aim. Cyclic decapeptides are suited as rigid carriers for carbohydrate derivatives. We herein document the bioactivity of sugar headgroups covalently attached to this carrier for the cases of five proteins, i.e. a potent biohazardous plant agglutinin, a leguminous model lectin and three adhesion/growth-regulatory human lectins. They represent the different types of topological organization within the galectin family. The relative inhibitory activities of glycoclusters with the three ligands (galactose, lactose and the disaccharide of the Thomsen-Friedenreich antigen) reflected the affinity of free carbohydrates, hereby excluding an impairment of binding activity by chemical derivatization and conjugation. Headgroup tailoring is thus one route to optimize activity and selectivity of cyclopeptide-based glycoclusters. The increase of ligand density from tetra- to hexadecavalency added a second route. The plant toxin and tandem-repeat-type galectin-4 were especially sensitive to this parameter change. Strategically combining solid-phase assays for screening with analysis of lectin binding to cells in different systems revealed efficient inhibition by distinct glycoclusters, thereby protecting cells from lectin association. Cyclic neoglycodecapeptides thus warrant further study as lectin-directed pharmaceuticals.Journal of Peptide Science 02/2011; 17(6):427-37. · 1.80 Impact Factor -
Article: Preparation of peptide and other biomolecular conjugates through chemoselective ligations.
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ABSTRACT: The synthesis of molecular conjugates through chemoselective ligations represents a very convenient strategy to prepare complex macromolecules with diverse functional elements. Herein, we describe chemical methods based on the preparation of chemoselectively addressable peptides allowing successive oxime ligations and/or alkyne-azide cycloaddition ("click") reactions of various biomolecules. This modular synthetic approach can be applied to a broad range of purposes.Methods in molecular biology (Clifton, N.J.) 01/2011; 751:67-79. -
Article: Dendri-RAFTs: a second generation of cyclopeptide-based glycoclusters.
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ABSTRACT: Synthetic glycoclusters and their related biological applications have stimulated increasing interest over the last decade. As a prerequisite to discovering active and selective therapeuticals, the development of multivalent glycoconjugates with diverse topologies is faced with inherent synthetic and structural characterisation difficulties. Here we describe a new series of molecularly-defined glycoclusters that were synthesized in a controlled manner using a robust and versatile divergent protocol. Starting from a Regioselectively Addressable Functionalized Template (RAFT) carrier, either a polylysine dendritic framework or a second RAFT, then 16 copies of βGal, αMan, βLac or cancer-related Thomsen-Freidenreich (αTF) antigen were successively conjugated within the same molecule using oxime chemistry. We thus obtained a new generation of dendri-RAFTs glycoclusters with high glycosidic density and variable spatial organizations. These compounds displaying 16 endgroups were unambiguously characterized by NMR spectroscopy and mass spectrometry. Further biological assays between a model lectin from Canavalia ensiformis (ConA) and mannosylated glycoclusters revealed a higher inhibition potency than the tetravalent counterpart, in particular for the hexadecavalent polylysine skeleton. Together with the efficiency of the synthetic and characterisation processes, this preliminary biological study provided clear evidence of promising properties that make the second generation of cyclopeptide-based glycoclusters attractive for biomedical applications.Organic & Biomolecular Chemistry 01/2011; 9(6):1948-59. · 3.70 Impact Factor -
Article: Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide.
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ABSTRACT: Metal overload plays an important role in several diseases or intoxications, like in Wilson's disease, a major genetic disorder of copper metabolism in humans. To efficiently and selectively decrease copper concentration in the liver that is highly damaged, chelators should be targeted at the hepatocytes. In the present work, we synthesized a molecule able to both lower intracellular copper, namely Cu(I), and target hepatocytes, combining within the same structure a chelating unit and a carbohydrate recognition element. A cyclodecapeptide scaffold displaying a controlled conformation with two independent faces was chosen to introduce both units. One face displays a cluster of carbohydrates to ensure an efficient recognition of the asialoglycoprotein receptors, expressed on the surface of hepatocytes. The second face is devoted to metal ion complexation thanks to the thiolate functions of two cysteine side-chains. To obtain a chelator that is active only once inside the cells, the two thiol functions were oxidized in a disulfide bridge to afford the glycopeptide P(3). Two simple cyclodecapeptides modeling the reduced and complexing form of P(3) in cells proved a high affinity for Cu(I) and a high selectivity with respect to Zn(II). As expected, P(3) becomes an efficient Cu(I) chelator in the presence of glutathione that mimics the intracellular reducing environment. Finally, cellular uptake and ability to lower intracellular copper were demonstrated in hepatic cell lines, in particular in WIF-B9, making P(3) a good candidate to fight copper overload in the liver.Journal of the American Chemical Society 12/2010; · 9.91 Impact Factor -
Article: Application of click-click chemistry to the synthesis of new multivalent RGD conjugates.
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ABSTRACT: New multivalent RGD-containing macromolecules were designed by exploiting two orthogonal chemoselective ligations. They were next applied to a competitive cell adhesion assay and used for the non invasive optical imaging of tumour in small animals.Organic & Biomolecular Chemistry 11/2010; 8(22):5133-8. · 3.70 Impact Factor -
Article: Synthesis of multivalent glycoconjugates containing the immunoactive LELTE peptide: effect of glycosylation on cellular activation and natural killing by human peripheral blood mononuclear cells.
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ABSTRACT: Pentapeptide diacidic sequence LELTE, derived from the mycobacterial heat shock protein hsp65, has been recently identified as a "danger" signal of the immune system effective via specific binding to the universal leukocyte triggering receptor CD69. This sequence is not active per se, only after its presentation within the multivalent environment of its parent protein, or after artificial dimerization using a standard bifunctional reagents. Here we describe an entirely new way of presenting of this peptide based on its attachment to a cyclopeptide RAFT scaffold (K-K-K-P-G)(2) through the epsilon-amino group of lysine residues, alone or in combination with the carbohydrate epitope alphaGalNAc. The ability of such RAFT scaffolds to precipitate the target CD69 receptor or to activate CD69-positive cells is enhanced in compounds 2 and 4 possessing combined peptide/carbohydrate expression. Compounds 2 and 4 are highly efficient activators of natural killer lymphocytes, but they are completely inactive from the point of view of activation-induced apoptosis of lymphocytes by the target cells. These unique properties make the combined peptide/carbohydrate RAFTs highly suitable for future evaluation in animal tumor therapies in vivo and predict them to be readily available and efficient immunoactivators.Journal of the American Chemical Society 05/2010; 132(19):6800-8. · 9.91 Impact Factor -
Article: Synthesis of Multivalent Glycoconjugates Containing the Immunoactive LELTE Peptide: Effect of Glycosylation on Cellular Activation and Natural Killing by Human Peripheral Blood Mononuclear Cells
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ABSTRACT: Pentapeptide diacidic sequence LELTE, derived from the mycobacterial heat shock protein hsp65, has been recently identified as a “danger” signal of the immune system effective via specific binding to the universal leukocyte triggering receptor CD69. This sequence is not active per se, only after its presentation within the multivalent environment of its parent protein, or after artificial dimerization using a standard bifunctional reagents. Here we describe an entirely new way of presenting of this peptide based on its attachment to a cyclopeptide RAFT scaffold (K-K-K-P-G)2 through the ε-amino group of lysine residues, alone or in combination with the carbohydrate epitope αGalNAc. The ability of such RAFT scaffolds to precipitate the target CD69 receptor or to activate CD69-positive cells is enhanced in compounds 2 and 4 possessing combined peptide/carbohydrate expression. Compounds 2 and 4 are highly efficient activators of natural killer lymphocytes, but they are completely inactive from the point of view of activation-induced apoptosis of lymphocytes by the target cells. These unique properties make the combined peptide/carbohydrate RAFTs highly suitable for future evaluation in animal tumor therapies in vivo and predict them to be readily available and efficient immunoactivators.04/2010; -
Article: Linear and branched glyco-lipopeptide vaccines follow distinct cross-presentation pathways and generate different magnitudes of antitumor immunity.
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ABSTRACT: 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.PLoS ONE 01/2010; 5(6):e11216. · 4.09 Impact Factor -
Article: Phenolic oxime oligomers inhibit Alzheimer's amyloid fibril formation and disaggregate fibrils in vitro.
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ABSTRACT: See you later amyloid beta: A screen of a small library of oxime oligomers with an HTS fluorescence assay for amyloid fibril inhibition and subsequent investigation by atomic force microscopy revealed two new micromolar inhibitors of amyloid fibril formation. These new inhibitors have IC(50) values in the 10 microM range.ChemBioChem 06/2009; 10(8):1325-9. · 3.94 Impact Factor -
Article: Biomolecular assembly by iterative oxime ligations.
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ABSTRACT: Herein we describe an iterative oxime-based procedure to prepare multivalent bioconjugates. Our approach is illustrated by the assembly of structurally diverse tetravalent and a new generation of hexadecavalent glycoclusters.Bioorganic & medicinal chemistry letters 04/2009; 19(14):3880-3. · 2.65 Impact Factor -
Article: Surface patterning of (bio)molecules onto the inner wall of fused-silica capillary tubes.
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ABSTRACT: An efficient photochemical method for the site-specific immobilization and patterning of (bio)molecules inside glass capillary tubes is reported. The strategy involves the photodeprotection of reactive aminooxy groups on surfaces and subsequent reaction with aldehyde containing (bio)molecules.Lab on a Chip 01/2009; 8(12):2161-3. · 5.67 Impact Factor -
Article: A cyclodecapeptide ligand to vitamin B12.
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ABSTRACT: Libraries of cyclic decapeptides were screened with vitamin B(12) derivatives to give cyclic peptide ligands incorporating histidine and cysteine as coordinating residues and negatively charged amino acids. Two hits, cyclo-(HisAspGluProGlyIleAlaThrProdGln) and cyclo-(ValAspGluProGlyGluAspCysProdGln) were resynthesized in good yields for solution experiments. The peptides bind aquocobalamin with coordination of His or Cys to the cobalt with high affinities (K(a) approximately 10(5) M(-1)). Additional interactions between the peptide side chains and the vitamin B(12) corrin moiety were determined by studying the (1)H NMR solution structure. The cyclopeptide-cobalamin complex with the histidine residue showed enhanced stability towards cyanide exchange, demonstrating the shielding effect of the ligand on the metal center.Organic & Biomolecular Chemistry 12/2008; 6(22):4134-41. · 3.70 Impact Factor -
Article: Oxime‐Based Synthesis of New Chromogenic and Fluorogenic Oligosaccharides
Annalen der Chemie und Pharmacie 09/2008; 2008(32):5383 - 5386. · 3.10 Impact Factor -
Article: Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes.
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ABSTRACT: Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants. In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing a chimeric peptide made of a CD8(+) T cell epitope, from ovalbumin (OVA(257-264)) and an universal CD4(+) T helper (Th) epitope (PADRE). The resulting CTL-Th peptide backbones was coupled to a carbohydrate B cell epitope based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules at C-terminal. The N terminus of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA(257-264)-specific IFN-gamma producing CD8(+) T cells; (3) PADRE-specific CD4(+) T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B Cell, CD4(+), and CD8(+) T cell epitopes-based immunotherapeutic cancer vaccines.Cancer Immunology and Immunotherapy 07/2008; 58(2):187-200. · 3.70 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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University of Bristol
- School of Chemistry
Bristol, ENG, United Kingdom
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2003–2012
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Université Joseph Fourier - Grenoble 1
- Département de chimie moléculaire
Grenoble, Rhone-Alpes, France
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2010
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University of California, Irvine
- Department of Medicine
Irvine, CA, USA
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2008
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University of Grenoble
Grenoble, Rhone-Alpes, France
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2003–2007
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Universität Bern
- Departement für Chemie und Biochemie
Bern, BE, Switzerland
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