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
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.
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U2 - 10.1038/NMAT5053
DO - 10.1038/NMAT5053
M3 - Article
AN - SCOPUS:85040925984
VL - 17
SP - 195
EP - 203
JO - Nature Materials
JF - Nature Materials
SN - 1476-1122
IS - 2
ER -