Franck Fieschi

Publications (50) View all

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  Article: Semen clusterin is a novel DC-SIGN ligand.

  Juan Sabatte, Wolfgang Faigle, Ana Ceballos, Willy Morelle, Christian Rodríguez Rodrígues, Federico Remes Lenicov, Michel Thépaut, Franck Fieschi, Emilio Malchiodi, Marisa Fernández, Fernando Arenzana-Seisdedos, Hugues Lortat-Jacob, Jean-Claude Michalski, Jorge Geffner, Sebastian Amigorena
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  ABSTRACT: The C-type lectin receptor dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is an important player in the recognition of pathogens by dendritic cells. A plethora of pathogens including viruses, bacteria, parasites, and fungi are recognized by DC-SIGN through both mannose and fucose-containing glycans expressed on the pathogen surface. In this study, we identified semen clusterin as a novel DC-SIGN ligand. Semen clusterin, but not serum clusterin, expresses an extreme abundance of fucose-containing blood-type Ags such as Le(x) and Le(y), which are both excellent DC-SIGN ligands. These motifs enable semen clusterin to bind DC-SIGN with very high affinity (K(d) 76 nM) and abrogate the binding of HIV-1 to DC-SIGN. Depletion of clusterin from semen samples, however, did not completely prevent the ability of semen to inhibit the capture of HIV-1 by DC-SIGN, supporting that besides clusterin, semen contains other DC-SIGN ligands. Further studies are needed to characterize these ligands and define their contribution to the DC-SIGN-blocking activity mediated by semen. Clusterin is an enigmatic protein involved in a variety of physiologic and pathologic processes including inflammation, atherosclerosis, and cancer. Our results uncover an unexpected heterogeneity in the glycosylation pattern of clusterin and suggest that the expression of high concentrations of fucose-containing glycans enables semen clusterin to display a unique set of biological functions that might affect the early course of sexually transmitted infectious diseases.
  The Journal of Immunology 11/2011; 187(10):5299-309. · 5.79 Impact Factor
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  Article: Insights into molecular recognition of Lewis(X) mimics by DC-SIGN using NMR and molecular modelling.

  Cinzia Guzzi, Jesús Angulo, Fabio Doro, José J Reina, Michel Thépaut, Franck Fieschi, Anna Bernardi, Javier Rojo, Pedro M Nieto
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  ABSTRACT: In this work, we have studied in detail the binding of two α-fucosylamide-based mimics of Lewis(X) to DC-SIGN ECD (ECD = extracellular domain) using STD NMR and docking. We have concluded that the binding mode occurs mainly through the fucose moiety, in the same way as Lewis(X). Similarly to other mimics containing mannose or fucose previously studied, we have shown that both compounds bind to DC-SIGN ECD in a multimodal fashion. In this case, the main contact is the interaction of two hydroxyl groups one equatorial and the other one axial (O3 and O4) of the fucose with the Ca(2+) as Lewis(X) and similarly to mannose-containing mimics (in this case the interacting groups are both in the equatorial position). Finally, we have measured the K(D) of one mimic that was 0.4 mM. Competitive STD NMR experiments indicate that the aromatic moiety provides additional binding contacts that increase the affinity.
  Organic & Biomolecular Chemistry 10/2011; 9(22):7705-12. · 3.70 Impact Factor
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  Article: Second generation of fucose-based DC-SIGN ligands: affinity improvement and specificity versus Langerin.

  Manuel Andreini, Daniela Doknic, Ieva Sutkeviciute, José J Reina, Janxin Duan, Eric Chabrol, Michel Thepaut, Elisabetta Moroni, Fabio Doro, Laura Belvisi, Joerg Weiser, Javier Rojo, Franck Fieschi, Anna Bernardi
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  ABSTRACT: DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (Le(X)). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection.
  Organic & Biomolecular Chemistry 08/2011; 9(16):5778-86. · 3.70 Impact Factor
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  Article: Pseudosaccharide functionalized dendrimers as potent inhibitors of DC-SIGN dependent Ebola pseudotyped viral infection.

  Joanna Luczkowiak, Sara Sattin, Ieva Sutkevičiūtė, José Juan Reina, Macarena Sánchez-Navarro, Michel Thépaut, Lorena Martínez-Prats, Anna Daghetti, Franck Fieschi, Rafael Delgado, Anna Bernardi, Javier Rojo
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  ABSTRACT: The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN.
  Bioconjugate Chemistry 06/2011; 22(7):1354-65. · 4.93 Impact Factor
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  Article: NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action.

  Vincent Jaquet, Julien Marcoux, Eric Forest, Kevin G Leidal, Sally McCormick, Yvonne Westermaier, Remo Perozzo, Olivier Plastre, Laetitia Fioraso-Cartier, Becky Diebold, Leonardo Scapozza, William M Nauseef, Franck Fieschi, Karl-Heinz Krause, Karen Bedard
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  ABSTRACT: Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions, and shows benefits in models of neurodegenerative disease, cancer and arthritis, although its mechanism of action is incompletely understood. Celastrol was tested on human NADPH oxidases (NOXs) using a panel of experiments: production of reactive oxygen species and oxygen consumption by NOX enzymes, xanthine oxidase activity, cell toxicity, phagocyte oxidase subunit translocation, and binding to cytosolic subunits of NOX enzymes. The effect of celastrol was compared with diphenyleneiodonium, an established inhibitor of flavoproteins. Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with concentration-response curves exhibiting higher Hill coefficients and lower IC₅₀ values for NOX1 and NOX2 compared with NOX4 and NOX5, suggesting differences in their mode of action. In a cell-free system, celastrol had an IC₅₀ of 1.24 and 8.4 µM for NOX2 and NOX5, respectively. Cytotoxicity, oxidant scavenging, and inhibition of p47(phox) translocation could not account for NOX inhibition. Celastrol bound to a recombinant p47(phox) and disrupted the binding of the proline rich region of p22(phox) to the tandem SH3 domain of p47(phox) and NOXO1, the cytosolic subunits of NOX2 and NOX1, respectively. These results demonstrate that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome.
  British Journal of Pharmacology 04/2011; 164(2b):507-20. · 4.41 Impact Factor