Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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 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

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (5MB) | Preview

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: Published Online
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 2045-2322
Date of First Compliant Deposit: 22 March 2018
Date of Acceptance: 20 February 2018
Last Modified: 26 Feb 2019 22:51
URI: http://orca.cf.ac.uk/id/eprint/110106

Citation Data

Cited 4 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics