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@article{reynard_mannoside_2018,

title = {Mannoside Glycolipid Conjugates Display Antiviral Activity Against Ebola Virus},

author = {Olivier Reynard and Evelyne Schaeffer and Valentina A Volchkova and Andrea Cimarelli and Christopher G Mueller and Viktor E Volchkov},

doi = {10.1093/infdis/jiy464},

issn = {1537-6613},

year  = {2018},

date = {2018-11-01},

journal = {The Journal of Infectious Diseases},

volume = {218},

number = {suppl_5},

pages = {S666--S671},

abstract = {The West African outbreak of Ebola virus (EBOV) infection during 2013-2016 highlighted the need for development of field-applicable therapeutic drugs for this infection. Here we report that mannoside glycolipid conjugates (MGCs) consisting of a trimannose head and a lipophilic chain assembled by a linker inhibit EBOV infection not only of human monocyte-derived dendritic cells and macrophages, but also of a number of susceptible cells. Analysis of the mode of action leads us to conclude that MGCs act directly on cells, notably by preventing virus endocytosis.},

keywords = {Animals, Antiviral Agents, Chlorocebus aethiops, Ebolavirus, Glycolipids, Humans, Mannosides, Team-Mueller, Vero Cells, Virus Internalization},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_inhibition_2018b,

title = {Inhibition of dengue virus infection by mannoside glycolipid conjugates},

author = {Evelyne Schaeffer and Vincent Flacher and Patrick Neuberg and Astrid Hoste and Adrien Brulefert and Jean-Daniel Fauny and Alain Wagner and Christopher G Mueller},

doi = {10.1016/j.antiviral.2018.04.005},

issn = {1872-9096},

year  = {2018},

date = {2018-01-01},

journal = {Antiviral Research},

volume = {154},

pages = {116--123},

abstract = {Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the inhibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV.},

keywords = {Animals, Antiviral Agents, Cell Line, Cell Membrane, Chemistry, Chlorocebus aethiops, Dendritic Cells, Dengue, Dengue virus, development, Drug, Drug Discovery, Flavivirus, function, Fusion, Glycolipids, Health, Hep G2 Cells, Human, Humans, immunopathology, infection, inhibition, inhibitors, Inhibitory Concentration 50, lipid, Macrophages, Mannosides, Membrane, Serogroup, Skin, Team-Mueller, vaccine, Vaccines, Vero Cells, viral Infection, virus, Virus Replication},

pubstate = {published},

tppubtype = {article}

}

@article{flacher_mannoside_2015b,

title = {Mannoside Glycolipid Conjugates Display Anti-inflammatory Activity by Inhibition of Toll-like Receptor-4 Mediated Cell Activation},

author = {Vincent Flacher and Patrick Neuberg and Floriane Point and François Daubeuf and Quentin Muller and David Sigwalt and Jean-Daniel Fauny and Jean-Serge Remy and Nelly Frossard and Alain Wagner and Christopher G Mueller and Evelyne Schaeffer},

doi = {10.1021/acschembio.5b00552},

issn = {1554-8937},

year  = {2015},

date = {2015-12-01},

journal = {ACS chemical biology},

volume = {10},

number = {12},

pages = {2697--2705},

abstract = {Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases.},

keywords = {Activation, Animals, Anti-Inflammatory Agents, Carbohydrate Sequence, CD14, Cell Membrane, Cells, Chemistry, Cultured, cytokine, Dendritic Cells, development, disease, Glycolipids, Human, Humans, immunopathology, Inbred BALB C, inflammation, inhibition, lipid, lipopolysaccharide, Lipopolysaccharides, LPS, LUNG, Mannosides, Maturation, Membrane, Mice, monocyte, Monocytes, mouse, neutrophils, NF-kappaB, Pneumonia, Protein-Serine-Threonine Kinases, Receptor, secretion, signaling, Structure-Activity Relationship, Tail, Team-Mueller, TLR4, Toll-Like Receptor 4},

pubstate = {published},

tppubtype = {article}

}

@article{schaeffer_dynamic_2013,

title = {Dynamic micelles of mannoside glycolipids are more efficient than polymers for inhibiting HIV-1 trans-infection},

author = {Evelyne Schaeffer and Laure Dehuyser and David Sigwalt and Vincent Flacher and Serena Bernacchi and Olivier Chaloin and Jean-Serge Remy and Christopher G Mueller and Rachid Baati and Alain Wagner},

doi = {10.1021/bc4000806},

issn = {1520-4812},

year  = {2013},

date = {2013-11-01},

journal = {Bioconjugate Chemistry},

volume = {24},

number = {11},

pages = {1813--1823},

abstract = {Mannoside glycolipid conjugates are able to inhibit human immunodeficiency virus type 1 (HIV-1) trans-infection mediated by human dendritic cells (DCs). The conjugates are formed by three building blocks: a linear or branched mannose head, a hydrophilic linker, and a 24-carbon lipid chain. We have shown that, even as single molecules, these compounds efficiently target mannose-binding lectins, such as DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) important for HIV-1 transmission. With the goal to optimize their inhibitory activity by supramolecular structure formation, we have compared saturated and unsaturated conjugates, as single molecules, self-assemblies of dynamic micelles, and photopolymerized cross-linked polymers. Surface plasmon resonance showed that, unexpectedly, polymers of trivalent conjugates did not display a higher binding affinity for DC-SIGN than single molecules. Interactions on a chip or in solution were independent of calcium; however, binding to DCs was inhibited by a calcium chelator. Moreover, HIV-1 trans-infection was mostly inhibited by dynamic micelles and not by rigid polymers. The inhibition data revealed a clear correlation between the structure and molecular assembly of a conjugate and its biological antiviral activity. We present an interaction model between DC-SIGN and conjugates-either single molecules, micelles, or polymers-that highlights that the most effective interactions by dynamic micelles involve both mannose heads and lipid chains. Our data reveal that trivalent glycolipid conjugates display the highest microbicide potential for HIV prophylaxis, as dynamic micelles conjugates and not as rigid polymers.},

keywords = {Anti-HIV Agents, Calcium, Cells, Chemistry, Cultured, Dendritic Cells, Dose-Response Relationship, Drug, Electron, fluorescence, Glycolipids, HIV, HIV Infections, HIV-1, Human, Humans, immunodeficiency, immunopathology, inhibition, LECTIN, Lectins, lipid, Mannosides, Micelles, Microbial Sensitivity Tests, Microscopy, Models, Molecular, Molecular Structure, Polymers, prophylaxis, Spectrometry, Structure-Activity Relationship, Surface Plasmon Resonance, target, Team-Mueller, Thermodynamics, Transmission, virus},

pubstate = {published},

tppubtype = {article}

}