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

Valeria Cagno; Patrizia Andreozzi; Marco D'Alicarnasso; Paulo Jacob Silva; Marie Mueller; Marie Galloux; Ronan Le Goffic; Samuel T. Jones; Marta Vallino; Jan Hodek; Jan Weber; Soumyo Sen; Emma Rose Janecek; Ahmet Bekdemir; Barbara Sanavio; Chiara Martinelli; Manuela Donalisio; Marie Anne Rameix Welti; Jean Francois Eleouet; Yanxiao Han; Laurent Kaiser; Lela Vukovic; Caroline Tapparel; Petr Král; Silke Krol; David Lembo; Francesco Stellacci

doi:10.1038/NMAT5053

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

Valeria Cagno, Patrizia Andreozzi, Marco D'Alicarnasso, Paulo Jacob Silva, Marie Mueller, Marie Galloux, Ronan Le Goffic, Samuel T. Jones, Marta Vallino, Jan Hodek, Jan Weber, Soumyo Sen, Emma Rose Janecek, Ahmet Bekdemir, Barbara Sanavio, Chiara Martinelli, Manuela Donalisio, Marie Anne Rameix Welti, Jean Francois Eleouet, Yanxiao HanLaurent Kaiser, Lela Vukovic, Caroline Tapparel, Petr Král, Silke Krol, David Lembo^*, Francesco Stellacci

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	195-203
Number of pages	9
Journal	Nature Materials
Volume	17
Issue number	2
DOIs	https://doi.org/10.1038/NMAT5053
Publication status	Published - 1 Feb 2018

Bibliographical note

Funding Information:
195 203 10.1038/nmat5053 EN Valeria Cagno Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Patrizia Andreozzi IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy CIC biomaGUNE Soft Matter Nanotechnology Group San Sebastian-Donostia, 20014 Donastia San Sebastián, Spain Marco D’Alicarnasso Fondazione Centro Europeo Nanomedicina (CEN), Milan, Italy Paulo Jacob Silva Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Marie Mueller Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Marie Galloux VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Ronan Le Goffic VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Samuel T. Jones Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Jones Lab, School of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK Marta Vallino Istituto per la Protezione Sostenibile delle Piante, CNR, Torino, Italy http://orcid.org/0000-0003-1465-3574 Jan Hodek Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic Jan Weber Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic http://orcid.org/0000-0002-2799-7352 Soumyo Sen Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Emma-Rose Janeček Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0002-9264-1803 Ahmet Bekdemir Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Barbara Sanavio Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-5837-4097 Chiara Martinelli IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-9360-1689 Manuela Donalisio Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Marie-Anne Rameix Welti UMR INSERM U1173 I2, UFR des Sciences de la Santé Simone Veil—UVSQ, Montigny-Le-Bretonneux, France AP-HP, Laboratoire de Microbiologie, Hôpital Ambroise Paré, 92104 Boulogne-Billancourt, France Jean-Francois Eleouet VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Yanxiao Han Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Laurent Kaiser Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Lela Vukovic Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968, USA Caroline Tapparel Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Petr Král Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Department of Physics and Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA Silke Krol Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy David Lembo Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Francesco Stellacci Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Interfaculty Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0003-4635-6080 nmat5053 10.1038/nmat5053 2016 12 22 2017 11 10 2017 December 18 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.

Funding Information:
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

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

ASJC Scopus subject areas

General Chemistry
General Materials Science
Condensed Matter Physics
Mechanics of Materials
Mechanical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/NMAT5053

Cite this

Cagno, V., Andreozzi, P., D'Alicarnasso, M., Silva, P. J., Mueller, M., Galloux, M., Goffic, R. L., Jones, S. T., Vallino, M., Hodek, J., Weber, J., Sen, S., Janecek, E. R., Bekdemir, A., Sanavio, B., Martinelli, C., Donalisio, M., Welti, M. A. R., Eleouet, J. F., ... Stellacci, F. (2018). Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. Nature Materials, 17(2), 195-203. https://doi.org/10.1038/NMAT5053

@article{2d5694a73298412397cd37d19d30e0fa,

title = "Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism",

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.",

author = "Valeria Cagno and Patrizia Andreozzi and Marco D'Alicarnasso and Silva, {Paulo Jacob} and Marie Mueller and Marie Galloux and Goffic, {Ronan Le} and Jones, {Samuel T.} and Marta Vallino and Jan Hodek and Jan Weber and Soumyo Sen and Janecek, {Emma Rose} and Ahmet Bekdemir and Barbara Sanavio and Chiara Martinelli and Manuela Donalisio and Welti, {Marie Anne Rameix} and Eleouet, {Jean Francois} and Yanxiao Han and Laurent Kaiser and Lela Vukovic and Caroline Tapparel and Petr Kr{\'a}l and Silke Krol and David Lembo and Francesco Stellacci",

note = "Funding Information: 195 203 10.1038/nmat5053 EN Valeria Cagno Dipartimento di Scienze Cliniche e Biologiche, Univerisit{\`a} degli Studi di Torino, Orbassano, Italy Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Patrizia Andreozzi IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy CIC biomaGUNE Soft Matter Nanotechnology Group San Sebastian-Donostia, 20014 Donastia San Sebasti{\'a}n, Spain Marco D{\textquoteright}Alicarnasso Fondazione Centro Europeo Nanomedicina (CEN), Milan, Italy Paulo Jacob Silva Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Marie Mueller Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Marie Galloux VIM, INRA, Universit{\'e} Paris-Saclay, Jouy-en-Josas, France Ronan Le Goffic VIM, INRA, Universit{\'e} Paris-Saclay, Jouy-en-Josas, France Samuel T. Jones Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Jones Lab, School of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK Marta Vallino Istituto per la Protezione Sostenibile delle Piante, CNR, Torino, Italy http://orcid.org/0000-0003-1465-3574 Jan Hodek Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic Jan Weber Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic http://orcid.org/0000-0002-2799-7352 Soumyo Sen Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Emma-Rose Jane{\v c}ek Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0002-9264-1803 Ahmet Bekdemir Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Barbara Sanavio Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-5837-4097 Chiara Martinelli IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-9360-1689 Manuela Donalisio Dipartimento di Scienze Cliniche e Biologiche, Univerisit{\`a} degli Studi di Torino, Orbassano, Italy Marie-Anne Rameix Welti UMR INSERM U1173 I2, UFR des Sciences de la Sant{\'e} Simone Veil—UVSQ, Montigny-Le-Bretonneux, France AP-HP, Laboratoire de Microbiologie, H{\^o}pital Ambroise Par{\'e}, 92104 Boulogne-Billancourt, France Jean-Francois Eleouet VIM, INRA, Universit{\'e} Paris-Saclay, Jouy-en-Josas, France Yanxiao Han Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Laurent Kaiser Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Lela Vukovic Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968, USA Caroline Tapparel Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Petr Kr{\'a}l Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Department of Physics and Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA Silke Krol Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy David Lembo Dipartimento di Scienze Cliniche e Biologiche, Univerisit{\`a} degli Studi di Torino, Orbassano, Italy Francesco Stellacci Institute of Materials, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland Interfaculty Bioengineering Institute, Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0003-4635-6080 nmat5053 10.1038/nmat5053 2016 12 22 2017 11 10 2017 December 18 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. Funding Information: 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 Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",

year = "2018",

month = feb,

day = "1",

doi = "10.1038/NMAT5053",

language = "English",

volume = "17",

pages = "195--203",

journal = "Nature Materials",

issn = "1476-1122",

publisher = "Nature Publishing Group",

number = "2",

}

Cagno, V, Andreozzi, P, D'Alicarnasso, M, Silva, PJ, Mueller, M, Galloux, M, Goffic, RL, Jones, ST, Vallino, M, Hodek, J, Weber, J, Sen, S, Janecek, ER, Bekdemir, A, Sanavio, B, Martinelli, C, Donalisio, M, Welti, MAR, Eleouet, JF, Han, Y, Kaiser, L, Vukovic, L, Tapparel, C, Král, P, Krol, S, Lembo, D & Stellacci, F 2018, 'Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism', Nature Materials, vol. 17, no. 2, pp. 195-203. https://doi.org/10.1038/NMAT5053

TY - JOUR

T1 - Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

AU - Cagno, Valeria

AU - Andreozzi, Patrizia

AU - D'Alicarnasso, Marco

AU - Silva, Paulo Jacob

AU - Mueller, Marie

AU - Galloux, Marie

AU - Goffic, Ronan Le

AU - Jones, Samuel T.

AU - Vallino, Marta

AU - Hodek, Jan

AU - Weber, Jan

AU - Sen, Soumyo

AU - Janecek, Emma Rose

AU - Bekdemir, Ahmet

AU - Sanavio, Barbara

AU - Martinelli, Chiara

AU - Donalisio, Manuela

AU - Welti, Marie Anne Rameix

AU - Eleouet, Jean Francois

AU - Han, Yanxiao

AU - Kaiser, Laurent

AU - Vukovic, Lela

AU - Tapparel, Caroline

AU - Král, Petr

AU - Krol, Silke

AU - Lembo, David

AU - Stellacci, Francesco

N1 - Funding Information: 195 203 10.1038/nmat5053 EN Valeria Cagno Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Patrizia Andreozzi IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy CIC biomaGUNE Soft Matter Nanotechnology Group San Sebastian-Donostia, 20014 Donastia San Sebastián, Spain Marco D’Alicarnasso Fondazione Centro Europeo Nanomedicina (CEN), Milan, Italy Paulo Jacob Silva Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Marie Mueller Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Marie Galloux VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Ronan Le Goffic VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Samuel T. Jones Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Jones Lab, School of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK Marta Vallino Istituto per la Protezione Sostenibile delle Piante, CNR, Torino, Italy http://orcid.org/0000-0003-1465-3574 Jan Hodek Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic Jan Weber Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic http://orcid.org/0000-0002-2799-7352 Soumyo Sen Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Emma-Rose Janeček Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0002-9264-1803 Ahmet Bekdemir Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Barbara Sanavio Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-5837-4097 Chiara Martinelli IFOM - FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milan, Italy http://orcid.org/0000-0001-9360-1689 Manuela Donalisio Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Marie-Anne Rameix Welti UMR INSERM U1173 I2, UFR des Sciences de la Santé Simone Veil—UVSQ, Montigny-Le-Bretonneux, France AP-HP, Laboratoire de Microbiologie, Hôpital Ambroise Paré, 92104 Boulogne-Billancourt, France Jean-Francois Eleouet VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France Yanxiao Han Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Laurent Kaiser Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Lela Vukovic Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968, USA Caroline Tapparel Faculty of Medicine of Geneva, Department of Microbiology and Molecular medicine, Geneva, Switzerland Geneva University Hospitals, Infectious Diseases Divisions, Geneva, Switzerland Petr Král Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA Department of Physics and Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA Silke Krol Fondazione IRCCS Istituto Neurologico “Carlo Besta”, IFOM-IEO Campus, Milan, Italy IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy David Lembo Dipartimento di Scienze Cliniche e Biologiche, Univerisità degli Studi di Torino, Orbassano, Italy Francesco Stellacci Institute of Materials, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Interfaculty Bioengineering Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland http://orcid.org/0000-0003-4635-6080 nmat5053 10.1038/nmat5053 2016 12 22 2017 11 10 2017 December 18 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. Funding Information: 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 Publisher Copyright: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040925984&partnerID=8YFLogxK

U2 - 10.1038/NMAT5053

DO - 10.1038/NMAT5053

M3 - Article

C2 - 29251725

AN - SCOPUS:85040925984

SN - 1476-1122

VL - 17

SP - 195

EP - 203

JO - Nature Materials

JF - Nature Materials

IS - 2

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this