The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide.

Abstract

Nitazoxanide is a thiazolide compound that was originally developed as an anti-parasitic agent, but has recently been repurposed for the treatment of influenza virus infections. Thought to exert its anti-influenza activity via the inhibition of hemagglutinin maturation and intracellular trafficking in infected cells, the effectiveness of nitazoxanide in treating patients with non-complicated influenza is currently being assessed in phase III clinical trials. Here, we describe the susceptibility of 210 seasonal influenza viruses to tizoxanide, the active circulating metabolite of nitazoxanide. An optimised cell culture-based focus reduction assay was used to determine the susceptibility of A(H1N1)pdm09, A(H3N2), and influenza B viruses circulating in the southern hemisphere from the period March 2014 to August 2016. Tizoxanide showed potent in vitro antiviral activity against all influenza viruses tested, including neuraminidase inhibitor-resistant viruses, allowing the establishment of a baseline level of susceptibility for each subtype. Median EC50 values (±IQR) of 0.48 μM (0.33-0.71), 0.62 μM (0.56-0.75), 0.66 μM (0.62-0.69), and 0.60 μM (0.51-0.67) were obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses respectively. There was no significant difference in the median baseline tizoxanide susceptibility for each influenza subtype tested. This is the first report on the susceptibility of circulating viruses to tizoxanide. The focus reduction assay format described is sensitive, robust, and less laborious than traditional cell based antiviral assays, making it highly suitable for the surveillance of tizoxanide susceptibility in circulating seasonal influenza viruses.

• Authors: Danielle Tilmanis, Carel van Baalen, Ding Yuan Oh, Jean-Francois Rossignol, Aeron C Hurt
• Journal: Antiviral research (Antiviral Res) Vol. 147 Pg. 142-148 (Nov 2017) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 28986103 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Nitro Compounds
• Thiazoles
• tizoxanide
• Neuraminidase
• nitazoxanide

Topics

• Animals
• Antiviral Agents (pharmacology, toxicity)
• Cell Survival (drug effects)
• Dogs
• Drug Resistance, Viral (drug effects)
• Enzyme Inhibitors (pharmacology)
• Humans
• Influenza A Virus, H1N1 Subtype (drug effects)
• Influenza A Virus, H3N2 Subtype (drug effects)
• Influenza B virus (drug effects)
• Lethal Dose 50
• Madin Darby Canine Kidney Cells
• Neuraminidase (antagonists & inhibitors)
• Neutralization Tests
• Nitro Compounds
• Reproducibility of Results
• Sensitivity and Specificity
• Thiazoles (metabolism, pharmacology, toxicity)