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

Ferla, Salvatore, Netzler, Natalie E., Ferla, Sebastiano, Veronese, Sofia, Tuipulotu, Daniel Enosi, Guccione, Salvatore, Brancale, Andrea, White, Peter A. and Bassetto, Marcella 2018. In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase. Scientific Reports 8 (4129) , 4129. 10.1038/s41598-018-22303-y

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license
Publisher: Nature Publishing Group
ISSN: 2045-2322
Date of First Compliant Deposit: 22 March 2018
Date of Acceptance: 20 February 2018
Last Modified: 17 Mar 2021 02:44

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