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Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection

Nature Chemistry volume 8, pages 50–57 (2016)Cite this article

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Abstract

The use of multivalent carbohydrate compounds to block cell-surface lectin receptors is a promising strategy to inhibit the entry of pathogens into cells and could lead to the discovery of novel antiviral agents. One of the main problems with this approach, however, is that it is difficult to make compounds of an adequate size and multivalency to mimic natural systems such as viruses. Hexakis adducts of [60]fullerene are useful building blocks in this regard because they maintain a globular shape at the same time as allowing control over the size and multivalency. Here we report water-soluble tridecafullerenes decorated with 120 peripheral carbohydrate subunits, so-called ‘superballs’, that can be synthesized efficiently from hexakis adducts of [60]fullerene in one step by using copper-catalysed azide–alkyne cycloaddition click chemistry. Infection assays show that these superballs are potent inhibitors of cell infection by an artificial Ebola virus with half-maximum inhibitory concentrations in the subnanomolar range.

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Figure 1: Synthesis of azide-substituted glycofullerene 9 appended with a long linker and mannose as the carbohydrate unit.
Figure 2: Synthetic pathway to azide-substituted glycofullerenes 15a and 15b with a short spacer.
Figure 3: Syntheses of the tridecafullerenes 17a–17c using CuAAC click chemistry.
Figure 4: 13C NMR spectrum of tridecafullerene 17a in DMSO-d6.
Figure 5: TEM images and DLS analysis of tridecafullerene 17a.
Figure 6: Biological study of tridecafullerenes 17a–17c.

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Acknowledgements

Financial support by the European Research Council (ERC-2012-ADG_320441 (Chirallcarbon), ITN-2008-213592 (CARMUSYS)), Ministerio de Economía y Competitividad (MINECO) of Spain (projects CTQ2014-52045-R, CTQ2011-23410 and CTQ2012-31914), the Comunidad Autónoma de Madrid (PHOTOCARBON project S2013/MIT-2841), Instituto de Salud Carlos III (ISCIII) (FIS PI1101580 and FIS1400708), the Agence National de la Recherche (ANR, Programme Blanc 2011), the International Center for Frontier Research in Chemistry and LabEx ‘Chimie des Systèmes Complexes’ is acknowledged. N.M. thanks the Alexander von Humboldt Foundation. S.P.V. and K.B. thank FNRS (FRIA fellowship).

Author information

Authors and Affiliations

  1. Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, Madrid, 28040, Spain

    Antonio Muñoz, Beatriz M. Illescas, Laura Rodríguez-Pérez & Nazario Martín

  2. Laboratory V-SAT (CAMB UMR 7199, CNRS), Labex Medalis, Université de Strasbourg, 74 Route du Rhin, Illkirch-Graffenstaden, 67401, France

    David Sigwalt & Jean-Serge Remy

  3. Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, Strasbourg, 67087, France

    David Sigwalt, Iwona Nierengarten, Michel Holler & Jean-François Nierengarten

  4. Laboratorio de Microbiología Molecular, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, 28041, Spain

    Joanna Luczkowiak & Rafael Delgado

  5. Département de Chimie, Laboratoire de Chimie Bio-Organique, University of Namur (FUNDP), rue de Bruxelles 61, Namur, B-5000, Belgium

    Kevin Buffet & Stéphane P. Vincent

  6. Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC – Universidad de Sevilla, Av. Américo Vespucio 49, Seville, 41092, Spain

    Javier Rojo

  7. IMDEA-Nanoscience, Campus Cantoblanco, Madrid, 28049, Spain

    Nazario Martín

Authors
  1. Antonio Muñoz
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Contributions

A.M., D.S., I.N., M.H. and K.B. carried out the synthesis and characterization of all the new derivatives. L.R.-P. and J.-S.R. realized and analysed the DLS and TEM. L.R.-P. realized the XPS analyses and contributed to the writing of the paper. J.L. and R.D. realized the biological and cytotoxicity studies. B.M.I., S.P.V., J.R., R.D., J.-F.N. and N.M. designed the project, supervised the work, discussed the data and wrote the manuscript.

Corresponding authors

Correspondence to Javier Rojo, Rafael Delgado, Jean-François Nierengarten or Nazario Martín.

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The authors declare no competing financial interests.

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Muñoz, A., Sigwalt, D., Illescas, B. et al. Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection. Nature Chem 8, 50–57 (2016). https://doi.org/10.1038/nchem.2387

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