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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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.
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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