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

Broad-spectrum non-nucleoside inhibitors for caliciviruses

Netzler, Natalie E., Enosi Tuipulotu, Daniel, Eltahla, Auda A., Lun, Jennifer H., Ferla, Salvatore, Brancale, Andrea, Urakova, Nadya, Frese, Michael, Strive, Tanja, Mackenzie, Jason M. and White, Peter A. 2017. Broad-spectrum non-nucleoside inhibitors for caliciviruses. Antiviral Research 146 , pp. 65-75. 10.1016/j.antiviral.2017.07.014

[img]
Preview
PDF - Accepted Post-Print Version
Download (4MB) | Preview

Abstract

Viruses of the Caliciviridae cause significant and sometimes lethal diseases, however despite substantial research efforts, specific antivirals are lacking. Broad-spectrum antivirals could combat multiple viral pathogens, offering a rapid solution when no therapies exist. The RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target as it is essential for viral replication and lacks mammalian homologs. To focus the search for pan-Caliciviridae antivirals, the RdRp was probed with non-nucleoside inhibitors (NNIs) developed against hepatitis C virus (HCV) to reveal both allosteric ligands for structure-activity relationship enhancement, and highly-conserved RdRp pockets for antiviral targeting. The ability of HCV NNIs to inhibit calicivirus RdRp activities was assessed using in vitro enzyme and murine norovirus cell culture assays. Results revealed that three NNIs which bound the HCV RdRp Thumb I (TI) site also inhibited transcriptional activities of six RdRps spanning the Norovirus, Sapovirus and Lagovirus genera of the Caliciviridae. These NNIs included JTK-109 (RdRp inhibition range: IC50 4.3–16.6 μM), TMC-647055 (IC50 range: 18.8–45.4 μM) and Beclabuvir (IC50 range: 23.8–>100 μM). In silico studies and site-directed mutagenesis indicated the JTK-109 binding site was within the calicivirus RdRp thumb domain, in a pocket termed Site-B, which is highly-conserved within all calicivirus RdRps. Additionally, RdRp inhibition assays revealed that JTK-109 was antagonistic with the previously reported RdRp inhibitor pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulfonate) tetrasodium salt (PPNDS), that also binds to Site-B. Moreover, like JTK-109, PPNDS was also a potent inhibitor of polymerases from six viruses spanning the three Caliciviridae genera tested (IC50 range: 0.1–2.3 μM). Together, this study demonstrates the potential for de novo development of broad-spectrum antivirals that target the highly-conserved RdRp thumb pocket, Site-B. We also revealed three broad-spectrum HCV NNIs that could be used as antiviral scaffolds for further development against caliciviruses and other viruses.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier Masson
ISSN: 0166-3542
Date of First Compliant Deposit: 25 September 2017
Date of Acceptance: 24 July 2017
Last Modified: 24 Jan 2020 13:30
URI: http://orca-mwe.cf.ac.uk/id/eprint/104974

Citation Data

Cited 8 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