Pseudo-Mannosylated DC-SIGN Ligands as Immunomodulants

A. Berzi, S. Ordanini, B. Joosten, D. Trabattoni, A. Cambi, A. Bernardi and M. Clerici

Scientific Reports 2016, 6, article number 35373; DOI:10.1038/srep35373


DC-SIGN, a C-type lectin mainly expressed by DCs, mediates antigen uptake and can induce specific immune responses, depending on the ligand involved. Owing to these properties, DC-SIGN is an attracting target for approaches aimed at tailoring the immune response towards specific immunologic outcomes. A multivalent DC-SIGN ligand (Polyman26), containing at its core a fluorescent “rod-like” spacer and able to inhibit DC-SIGN mediated HIV infection in nanomolar concentration, has been recently developed by our group. We investigated the internalization pattern and the ability of Polyman26 to elicit innate immune responses. Results obtained by confocal microscopy indicate that Polyman26 is internalized by DCs via receptor- mediated endocytosis and is then routed to endolysosomal compartments, thus being presented together with MHC class II molecules, with important implications for the development of vaccines. Moreover, Polyman26 up-regulated the production of β-chemokines and pro-inflammatory cytokines (including IL-1β, IL-6, IL-12, and TNFα) as well as the expression of TLR9 and CD40L. These results indicate that glycomimetic DC-SIGN ligands should be further investigated and suggest that these compounds could be used to differentially stimulate immune responses.


Influence of Core β-1,2-Xylosylation on Glycoprotein Recognition by Murine C-type Lectin Receptors and Its Impact on Dendritic Cell Targeting

Brzezicka K, Vogel U, Serna S, Johannssen T, Lepenies B, Reichardt NC

ACS Chem Biol. 2016, 11(8), 2347-56


Targeting antigens to dendritic cell subsets is a promising strategy to enhance the efficacy of vaccines. C-type lectin receptors (CLRs) expressed by dendritic cells are particularly attractive candidates since CLR engagement may promote cell uptake and may further stimulate antigen presentation and subsequent T cell activation. While most previous approaches have involved antibody-mediated CLR-targeting, glycan-based CLR targeting has become more and more attractive in recent years. In the present study, we show that small structural glycan modifications may markedly influence CLR recognition, dendritic cell targeting, and subsequent T cell activation. A biantennary N-glycan (G0) and its analogous O-2 core xylosylated N-glycan (XG0) were synthesized, covalently conjugated to the model antigen ovalbumin, and analyzed for binding to a set of murine CLR-Fc fusion proteins using lectin microarray. To evaluate whether the differential binding of G0 and XG0 to CLRs impacted dendritic cell targeting, uptake studies using murine dendritic cells were performed. Finally, effects of the ovalbumin glycoconjugates on T cell activation were measured in a dendritic cell/T cell cocultivation assay. Our results highlight the utility of glycan-based dendritic cell targeting and demonstrate that small structural differences may have a major impact on dendritic cell targeting efficacy.

Paper NR-BL

Opportunities for glyconanomaterials in personalized medicine

Niels-Christian Reichardt, Manuel Martín-Lomas and Soledad Penadés

Chem. Commun., 2016,52, 13430-13439 DOI: 10.1039/C6CC04445J


In this feature article we discuss the particular relevance of glycans as components or targets of functionalized nanoparticles (NPs) for potential applications in personalized medicine but we will not enter into descriptions for their preparation. For a more general view covering the preparation and applications of glyconanomaterials the reader is referred to a number of recent reviews. The combination of glyco- and nanotechnology is already providing promising new tools for more personalized solutions to diagnostics and therapy. Current applications relevant to personalized medicine include drug targeting, localized radiation therapy, imaging of glycan expression of cancer cells, point of care diagnostics, cancer vaccines, photodynamic therapy, biosensors, and glycoproteomics.

Paper NR

Rapid and efficient synthesis of α(1–2) mannobiosides

José J. Reina, Antonio Di Maio, Javier Ramos-Soriano, Rute C. Figueiredo and Javier Rojo

Org. Biomol. Chem. 2016 DOI: 10.1039/c6ob00083e

α(1,2)mannobiosides with different substituents at the reducing end have been synthesized by a common strategy using benzoyls as the permanent protecting groups and an acetyl as the orthogonal protecting group at position C2 of the glycosyl acceptor. The new synthetic strategy has been performed remarkably reducing the number of purification steps, the time of synthesis (less than 72 hours) and improving the overall yield at least three times with respect to the best procedure described in the literature at the moment. Additionally, this protecting group strategy is compatible with the presence of azido groups and the use of Cu catalyzed azide alkyne cycloaddition (CuAAC) also called “click chemistry” for conjugating the α(1–2)mannobiosides to different scaffolds for the preparation of mannosyl multivalent systems.

Picture Paper Antonio

Designing nanomolar antagonists of DC-SIGN-mediated HIV infection: ligand presentation using molecular rods

Authors: Stefania Ordanini, Norbert Varga, Vanessa Porkolab, Michel Thépaut, Laura Belvisi, Andrea Bertaglia, Alessandro Palmioli, Angela Berzi, Daria Trabattoni, Mario Clerici, Franck Fieschi and Anna Bernardi

Journal: Chem. Commun., 2015, 51, 3816


DC-SIGN antagonists were designed combining one selective monovalent glycomimetic ligand with trivalent dendrons separated by a rigid core of controlled length. The design combines multiple multivalency effects to achieve inhibitors of HIV infection, which are active in nanomolar concentration.

Synthesis and Microarray-Assisted Binding Studies of Core Xylose and Fucose Containing N‑Glycans

Authors: Katarzyna Brzezicka, Begoña Echeverria, Sonia Serna, Angela van Diepen, Cornelis H. Hokke, and Niels-Christian Reichardt
Journal: ACS Chem. Biol. 2015 DOI: 10.1021/cb501023u


The synthesis of a collection of 33 xylosylated and core-fucosylated N-glycans found only in nonmammalian organisms such as plants and parasitic helminths has been achieved by employing a highly convergent chemo-enzymatic approach. The influence of these core modifications on the interaction with plant lectins, with the human lectin DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin), and with serum antibodies from schistosomeinfected individuals was studied. Core xylosylation markedly reduced or completely abolished binding to several mannosebinding plant lectins and to DC-SIGN, a C-type lectin receptor present on antigen presenting cells. Employing the synthetic collection of core-fucosylated and core-xylosylated N-glycans in the context of a larger glycan array including structures lacking these core modifications, we were able to dissect core xylose and core fucose specific antiglycan antibody responses in S. mansoni infection sera, and we observed clear and immunologically relevant differences between children and adult groups infected with this parasite. The work presented here suggests that, quite similar to bisecting N-acetylglucosamine, core xylose distorts the conformation of the unsubstituted glycan, with important implications for the immunogenicity and protein binding properties of complex N-glycans. DC-SIGN antagonists were designed combining one selective monovalent glycomimetic ligand with trivalent dendrons separated by a rigid core of controlled length. The design combines multiple multivalency effects to achieve inhibitors of HIV infection, which are active in nanomolar concentration.

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