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Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

Nature Materials volume 17, pages 195–203 (2018)Cite this article

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Abstract

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus–cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (∼190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

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Figure 1: Virucidal activity of MUS:OT-NPs.
Figure 2: HSV-2 and its association with MUS:OT-NPs.
Figure 3: Molecular dynamics simulations.
Figure 4: MUS:OT-NPs activity ex vivo and in vivo.

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Acknowledgements

F.S. and his laboratory were supported in part by the Swiss National Science Foundation NRP 64 grant, and by the NCCR on bio-inspired materials. D.L. was supported by a grant from University of Turin (ex 60%). J.H. and J.W. were supported by a research grant from the Ministry of Education, Youth and Sports of the Czech Republic (LK11207). C.T., L.K. and F.S. were supported by the Leenaards Foundation. P.K. was supported by the NSF DMR-1506886 grant. L.V. was supported by startup funding from UTEP. M.G. and R.L. thank the MIMA2 platform for access to the IVIS 200, which was financed by the Ile de France region (SESAME). M.M. thanks R. C. Guerrero-Ferreira for the tomogram acquisition. P.A. was supported by funding from the European Union Horizon, H2020 Nanofacturing, under grant agreement 646364.

Author information

Author notes

  1. Valeria Cagno and Patrizia Andreozzi: These authors contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy

    Valeria Cagno, Manuela Donalisio & David Lembo

  2. Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Valeria Cagno, Paulo Jacob Silva, Marie Mueller, Samuel T. Jones, Emma-Rose Janeček, Ahmet Bekdemir & Francesco Stellacci

  3. Department of Microbiology and Molecular medicine, Faculty of Medicine of Geneva, Geneva, Switzerland

    Valeria Cagno & Caroline Tapparel

  4. IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy

    Patrizia Andreozzi & Chiara Martinelli

  5. CIC biomaGUNE Soft Matter Nanotechnology Group San Sebastian-Donostia, 20014 Donastia San Sebastián, Spain

    Patrizia Andreozzi

  6. Fondazione Centro Europeo Nanomedicina (CEN), Milan, Italy

    Marco D’Alicarnasso

  7. VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France

    Marie Galloux, Ronan Le Goffic & Jean-Francois Eleouet

  8. Jones Lab, School of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK

    Samuel T. Jones

  9. Istituto per la Protezione Sostenibile delle Piante, CNR, Torino, Italy

    Marta Vallino

  10. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

    Jan Hodek & Jan Weber

  11. Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA

    Soumyo Sen, Yanxiao Han & Petr Král

  12. Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy

    Barbara Sanavio & Silke Krol

  13. UMR INSERM U1173 I2, UFR des Sciences de la Santé Simone Veil—UVSQ, Montigny-Le-Bretonneux, France

    Marie-Anne Rameix Welti

  14. AP-HP, Laboratoire de Microbiologie, Hôpital Ambroise Paré, 92104 Boulogne-Billancourt, France

    Marie-Anne Rameix Welti

  15. Infectious Diseases Divisions, Geneva University Hospitals, Geneva, Switzerland

    Laurent Kaiser & Caroline Tapparel

  16. Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968, USA

    Lela Vukovic

  17. Department of Physics and Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA

    Petr Král

  18. IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

    Silke Krol

  19. Interfaculty Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Francesco Stellacci

Authors
  1. Valeria Cagno
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Contributions

V.C. was responsible for all activities involving HSV2, HPV and RSV under the supervision of D.L. and EpiVaginal experiments under the supervision of C.T. and L.K. P.A. M.D. and C.M. were responsible for all testing with VSV-LV-G under the direction of S.K. P.J.S. was responsible for NP and ligand synthesis. M.M. was responsible for all cryo-TEM. S.T.J. was responsible for iron oxide NP synthesis. M.G. and R.L. were responsible for the in vivo experiments, R.W.M. and J.F.E. engineered the RSV-Luc used for in vivo experiments. M.V. was responsible for stained TEM imaging of the viruses. J.H. and J.W. conducted all testing with DENV-2. S.S. and Y.H. were responsible for molecular dynamics simulations under the direction of P.K., and L.V. E.R.J. and S.T.J. synthesized MUP-NPs. A.B. synthesized MES-NPs. B.S. synthesized EG2OH-NPs. M.D. was responsible for HSV-1 and HSV-2 and dose response experiments. F.S. and S.K. first conceived the experiments, F.S. and D.L. developed the interpretation of the experiments. F.S., D.L., V.C. and S.T.J. wrote the paper.

Corresponding authors

Correspondence to David Lembo or Francesco Stellacci.

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The authors declare no competing financial interests.

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Cagno, V., Andreozzi, P., D’Alicarnasso, M. et al. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. Nature Mater 17, 195–203 (2018). https://doi.org/10.1038/nmat5053

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