In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase

Abstract Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdR...

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Autores principales:	Salvatore Ferla, Natalie E. Netzler, Sebastiano Ferla, Sofia Veronese, Daniel Enosi Tuipulotu, Salvatore Guccione, Andrea Brancale, Peter A. White, Marcella Bassetto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/77b2d570609640eb84832ed1a696b6b2
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spelling	oai:doaj.org-article:77b2d570609640eb84832ed1a696b6b22021-12-02T15:08:00ZIn silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase10.1038/s41598-018-22303-y2045-2322https://doaj.org/article/77b2d570609640eb84832ed1a696b6b22018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-22303-yhttps://doaj.org/toc/2045-2322Abstract Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 µM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 µM), with the best candidate, 54, demonstrating an IC50 of 5.6 µM against the RdRp and a CC50 of 62.8 µM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral.Salvatore FerlaNatalie E. NetzlerSebastiano FerlaSofia VeroneseDaniel Enosi TuipulotuSalvatore GuccioneAndrea BrancalePeter A. WhiteMarcella BassettoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Salvatore Ferla Natalie E. Netzler Sebastiano Ferla Sofia Veronese Daniel Enosi Tuipulotu Salvatore Guccione Andrea Brancale Peter A. White Marcella Bassetto In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
description	Abstract Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 µM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 µM), with the best candidate, 54, demonstrating an IC50 of 5.6 µM against the RdRp and a CC50 of 62.8 µM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral.
format	article
author	Salvatore Ferla Natalie E. Netzler Sebastiano Ferla Sofia Veronese Daniel Enosi Tuipulotu Salvatore Guccione Andrea Brancale Peter A. White Marcella Bassetto
author_facet	Salvatore Ferla Natalie E. Netzler Sebastiano Ferla Sofia Veronese Daniel Enosi Tuipulotu Salvatore Guccione Andrea Brancale Peter A. White Marcella Bassetto
author_sort	Salvatore Ferla
title	In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
title_short	In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
title_full	In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
title_fullStr	In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
title_full_unstemmed	In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
title_sort	in silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/77b2d570609640eb84832ed1a696b6b2
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In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase

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