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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.

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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.

References

  1. Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet (London, England) 380, 2095–2128 (2012).

    Article  Google Scholar 

  2. Top 10 causes of death. WHOhttp://www.who.int/mediacentre/factsheets/fs310/en (2017).

  3. Plotkin, S. A. Vaccines: past, present and future. Nat. Med. 11, S5–S11 (2005).

    CAS  Article  Google Scholar 

  4. De Clercq, E. & Li, G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 29, 695–747 (2016).

    Article  Google Scholar 

  5. De Clercq, E. Strategies in the design of antiviral drugs. Nat. Rev. Drug Discov. 1, 13–25 (2002).

    CAS  Article  Google Scholar 

  6. Fridland, A., Connelly, M. C. & Robbins, B. L. Cellular factors for resistance against antiretroviral agents. Antivir. Ther. 5, 181–185 (2000).

    CAS  Google Scholar 

  7. Spillmann, D. Heparan sulfate: anchor for viral intruders? Biochimie 83, 811–817 (2001).

    CAS  Article  Google Scholar 

  8. Cagno, V. et al. Highly sulfated K5 Escherichia coli polysaccharide derivatives inhibit respiratory syncytial virus infectivity in cell lines and human tracheal-bronchial histocultures. Antimicrob. Agents Chemother. 58, 4782–4794 (2014).

    Article  CAS  Google Scholar 

  9. Lembo, D. et al. Auto-associative heparin nanoassemblies: a biomimetic platform against the heparan sulfate-dependent viruses HSV-1, HSV-2, HPV-16 and RSV. Eur. J. Pharmaceutics Biopharmaceutics: Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik e.V 88, 275–282 (2014).

    CAS  Article  Google Scholar 

  10. Rusnati, M. et al. Sulfated K5 Escherichia coli polysaccharide derivatives: a novel class of candidate antiviral microbicides. Pharmacol. Ther. 123, 310–322 (2009).

    CAS  Article  Google Scholar 

  11. Klimyte, E. M., Smith, S. E., Oreste, P., Lembo, D. & Dutch, R. E. Inhibition of human metapneumovirus binding to heparan sulfate blocks infection in human lung cells and airway tissues. J. Virol. 90, 9237–9250 (2016).

    CAS  Article  Google Scholar 

  12. Riblett, A. M. et al. A haploid genetic screen identifies heparan sulfate proteoglycans supporting Rift Valley fever virus infection. J. Virol. 90, 1414–1423 (2015).

    Article  CAS  Google Scholar 

  13. Donalisio, M. et al. The AGMA1 poly(amidoamine) inhibits the infectivity of herpes simplex virus in cell lines, in human cervicovaginal histocultures, and in vaginally infected mice. Biomaterials 85, 40–53 (2016).

    CAS  Article  Google Scholar 

  14. Cagno, V. et al. The agmatine-containing poly(amidoamine) polymer AGMA1 binds cell surface heparan sulfates and prevents attachment of mucosal human papillomaviruses. Antimicrob. Agents Chemother. 59, 5250–5259 (2015).

    CAS  Article  Google Scholar 

  15. Baram-Pinto, D., Shukla, S., Gedanken, A. & Sarid, R. Inhibition of HSV-1 attachment, entry, and cell-to-cell spread by functionalized multivalent gold nanoparticles. Small 6, 1044–1050 (2010).

    CAS  Article  Google Scholar 

  16. Bergstrom, D. E. et al. Polysulfonates derived from metal thiolate complexes as inhibitors of HIV-1 and various other enveloped viruses in vitro. Antivir. Chem. Chemother. 13, 185–195 (2002).

    CAS  Article  Google Scholar 

  17. Bowman, M.-C. et al. Inhibition of HIV fusion with multivalent gold nanoparticles. J. Am. Chem. Soc. 130, 6896–6897 (2008).

    CAS  Article  Google Scholar 

  18. Scordi-Bello, I. A. et al. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob. Agents Chemother. 49, 3607–3615 (2005).

    CAS  Article  Google Scholar 

  19. McCormack, S. et al. PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. Lancet 376, 1329–1337 (2010).

    CAS  Article  Google Scholar 

  20. Pirrone, V., Wigdahl, B. & Krebs, F. C. The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1. Antivir. Res. 90, 168–182 (2011).

    CAS  Article  Google Scholar 

  21. Van Damme, L. et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. New Engl. J. Med. 359, 463–472 (2008).

    CAS  Article  Google Scholar 

  22. Shogan, B., Kruse, L., Mulamba, G. B., Hu, A. & Coen, D. M. Virucidal activity of a GT-rich oligonucleotide against herpes simplex virus mediated by glycoprotein B. J. Virol. 80, 4740–4747 (2006).

    CAS  Article  Google Scholar 

  23. Bastian, A. R. et al. Cell-free HIV-1 virucidal action by modified peptide triazole inhibitors of Env gp120. ChemMedChem 6, 1335–1339 (2011).

    CAS  Article  Google Scholar 

  24. de Souza e Silva, J. M. et al. Viral inhibition mechanism mediated by surface-modified silica nanoparticles. ACS Appl. Mater. Interfaces 8, 16564–16572 (2016).

    Article  CAS  Google Scholar 

  25. Bromberg, L. et al. Antiviral properties of polymeric aziridine- and biguanide-modified core-shell magnetic nanoparticles. Langmuir 28, 4548–4558 (2012).

    CAS  Article  Google Scholar 

  26. Broglie, J. J. et al. Antiviral activity of gold/copper sulfide core/shell nanoparticles against human norovirus virus-like particles. PLoS ONE 10, e0141050 (2015).

    Article  CAS  Google Scholar 

  27. Lara, H. H., Garza-Trevino, E. N., Ixtepan-Turrent, L. & Singh, D. K. Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds. J. Nanobiotechnology 9, 30 (2011).

    CAS  Article  Google Scholar 

  28. Chen, N. N., Zheng, Y., Yin, J. J., Li, X. J. & Zheng, C. L. Inhibitory effects of silver nanoparticles against adenovirus type 3 in vitro. J. Virol. Methods 193, 470–477 (2013).

    CAS  Article  Google Scholar 

  29. Abe, M. et al. Effects of several virucidal agents on inactivation of influenza, Newcastle disease, and avian infectious bronchitis viruses in the allantoic fluid of chicken eggs. Jpn. J. Infect. Dis. 60, 342–346 (2007).

    Google Scholar 

  30. Chaudhuri, A., Battaglia, G. & Golestanian, R. The effect of interactions on the cellular uptake of nanoparticles. Phys. Biol. 8, 046002 (2011).

    Article  CAS  Google Scholar 

  31. Lipowsky, R. & Dobereiner, H. G. Vesicles in contact with nanoparticles and colloids. Europhys. Lett. 43, 219–225 (1998).

    CAS  Article  Google Scholar 

  32. Sabella, S. et al. A general mechanism for intracellular toxicity of metal-containing nanoparticles. Nanoscale 6, 7052–7061 (2014).

    CAS  Article  Google Scholar 

  33. Huang, R. X., Carney, R. P., Stellacci, F. & Lau, B. L. T. Colloidal stability of self-assembled mono layer-coated gold nanoparticles: the effects of surface compositional and structural heterogeneity. Langmuir 29, 11560–11566 (2013).

    CAS  Article  Google Scholar 

  34. Huang, R. X., Carney, R. P., Stellacci, F. & Lau, B. L. T. Protein-nanoparticle interactions: the effects of surface compositional and structural heterogeneity are scale dependent. Nanoscale 5, 6928–6935 (2013).

    CAS  Article  Google Scholar 

  35. Huang, R. X., Carney, R. R., Ikuma, K., Stellacci, F. & Lau, B. L. T. Effects of surface compositional and structural heterogeneity on nanoparticle-protein interactions: different protein configurations. ACS Nano 8, 5402–5412 (2014).

    CAS  Article  Google Scholar 

  36. Bathia, S., Cuellar Camacho, L. & Haag, R. Pathogen inhibition by multivalent ligand architectures. J. Am. Chem. Soc. 138, 8654–8666 (2016).

    Article  CAS  Google Scholar 

  37. Dasgupta, J. et al. Structural basis of oligosaccharide receptor recognition by human papillomavirus. J. Biol. Chem. 286, 2617–2624 (2011).

    CAS  Article  Google Scholar 

  38. Knappe, M. et al. Surface-exposed amino acid residues of HPV16 l1 protein mediating interaction with cell surface heparan sulfate. J. Biol. Chem. 282, 27913–27922 (2007).

    CAS  Article  Google Scholar 

  39. Qian, E. Q. et al. Atomically precise organomimetic cluster nanomolecules assembled via Perfluoroaryl-Thiol SNAr Chemistry. Nat. Chem. 9, 333–340 (2016).

    Article  CAS  Google Scholar 

  40. Matulis, D. & Lovrien, R. 1-Anilino-8-naphthalene sulfonate anion-protein binding depends primarily on ion pair formation. Biophys. J. 74, 422–429 (1998).

    CAS  Article  Google Scholar 

  41. Melcrova, A. et al. The complex nature of calcium cation interactions with phospholipid bilayers. Sci. Rep. 6, 38035 (2016).

    CAS  Article  Google Scholar 

  42. Verma, A. et al. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nat. Mater. 7, 588–595 (2008).

    CAS  Article  Google Scholar 

  43. Rameix-Welti, M.-A. et al. Visualizing the replication of respiratory syncytial virus in cells and in living mice. Nat. Commun. 5, 5104 (2014).

    CAS  Article  Google Scholar 

Download references

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.

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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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