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.

AP HP Laboratoire de Microbiologie Hôpital Ambroise Paré 92104 Boulogne Billancourt France

CIC biomaGUNE Soft Matter Nanotechnology Group San Sebastian Donostia 20014 Donastia San Sebastián Spain

Department of Chemistry University of Illinois at Chicago Chicago Illinois 60607 USA

Department of Chemistry University of Texas at El Paso El Paso Texas 79968 USA

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

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

Faculty of Medicine of Geneva Department of Microbiology and Molecular medicine Geneva Switzerland

Fondazione Centro Europeo Nanomedicina Milan Italy

Fondazione IRCCS Istituto Neurologico Carlo Besta IFOM IEO Campus Milan Italy

Geneva University Hospitals Infectious Diseases Divisions Geneva Switzerland

IFOM FIRC Institute of Molecular Oncology IFOM IEO Campus Milan Italy

Institute of Materials Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

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

Interfaculty Bioengineering Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

IRCCS Istituto Tumori Giovanni Paolo 2 Bari Italy

Istituto per la Protezione Sostenibile delle Piante CNR Torino Italy

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

UMR INSERM U1173 I2 UFR des Sciences de la Santé Simone Veil UVSQ Montigny Le Bretonneux France

VIM INRA Université Paris Saclay Jouy en Josas France

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Nat Mater. 2018 Jan 23;17(2):114-116. doi: 10.1038/nmat5064. PubMed

Zobrazit více v PubMed

J Virol. 2006 May;80(10):4740-7 PubMed

Lancet. 2010 Oct 16;376(9749):1329-37 PubMed

Antimicrob Agents Chemother. 2014 Aug;58(8):4782-94 PubMed

Biophys J. 1998 Jan;74(1):422-9 PubMed

ACS Appl Mater Interfaces. 2016 Jul 6;8(26):16564-72 PubMed

Nanoscale. 2014 Jun 21;6(12):7052-61 PubMed

Antivir Ther. 2000 Sep;5(3):181-5 PubMed

ChemMedChem. 2011 Aug 1;6(8):1335-9, 1318 PubMed

Langmuir. 2013 Sep 17;29(37):11560-6 PubMed

Nat Commun. 2014 Oct 03;5:5104 PubMed

Nat Chem. 2017 Apr;9(4):333-340 PubMed

Small. 2010 May 7;6(9):1044-50 PubMed

Biomaterials. 2016 Apr;85:40-53 PubMed

Biochimie. 2001 Aug;83(8):811-7 PubMed

J Biol Chem. 2007 Sep 21;282(38):27913-22 PubMed

Langmuir. 2012 Mar 6;28(9):4548-58 PubMed

N Engl J Med. 2008 Jul 31;359(5):463-72 PubMed

Antiviral Res. 2011 Jun;90(3):168-82 PubMed

J Am Chem Soc. 2016 Jul 20;138(28):8654-66 PubMed

Nat Mater. 2008 Jul;7(7):588-95 PubMed

Phys Biol. 2011 Aug;8(4):046002 PubMed

Lancet. 2012 Dec 15;380(9859):2095-128 PubMed

Nanoscale. 2013 Aug 7;5(15):6928-35 PubMed

Eur J Pharm Biopharm. 2014 Sep;88(1):275-82 PubMed

Pharmacol Ther. 2009 Sep;123(3):310-22 PubMed

ACS Nano. 2014 Jun 24;8(6):5402-12 PubMed

Antimicrob Agents Chemother. 2015 Sep;59(9):5250-9 PubMed

J Biol Chem. 2011 Jan 28;286(4):2617-24 PubMed

Antivir Chem Chemother. 2002 May;13(3):185-95 PubMed

Clin Microbiol Rev. 2016 Jul;29(3):695-747 PubMed

Nat Med. 2005 Apr;11(4 Suppl):S5-11 PubMed

J Virol. 2016 Sep 29;90(20):9237-50 PubMed

J Virol Methods. 2013 Nov;193(2):470-7 PubMed

Antimicrob Agents Chemother. 2005 Sep;49(9):3607-15 PubMed

J Nanobiotechnology. 2011 Aug 03;9:30 PubMed

J Virol. 2015 Nov 18;90(3):1414-23 PubMed

Sci Rep. 2016 Dec 01;6:38035 PubMed

Nat Rev Drug Discov. 2002 Jan;1(1):13-25 PubMed

PLoS One. 2015 Oct 16;10(10):e0141050 PubMed

Jpn J Infect Dis. 2007 Nov;60(6):342-6 PubMed

J Am Chem Soc. 2008 Jun 4;130(22):6896-7 PubMed

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