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

Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Netzler, Natalie E., Ferla, Sebastiano ORCID: https://orcid.org/0000-0002-5918-9237, Veronese, Sofia, Tuipulotu, Daniel Enosi, Guccione, Salvatore, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, White, Peter A. and Bassetto, Marcella ORCID: https://orcid.org/0000-0002-2491-5868 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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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.

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: 06 Jan 2024 05:05
URI: https://orca.cardiff.ac.uk/id/eprint/110106

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