Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence
Anna Riccio, Silvia Santopolo, Antonio Rossi, Sara Piacentini, Jean-Francois Rossignol, M Gabriella Santoro
Cellular and Molecular Life Sciences, doi:10.1007/s00018-022-04246-w
SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanideinduced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.
Statistical analysis Statistical analysis was performed using the Student's t test for unpaired data or one-way ANOVA test (Prism 5.0 software, GraphPad). Data are expressed as the mean ± SD of samples derived from at least three biological repeats and P values ≤ 0.05 were considered significant. All the results shown are representative of at least three independent experiments, each in duplicate or triplicate.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s00018-022-04246-w. Author contributions AR, SS and SP performed the analysis of protein synthesis, maturation and intracellular localization; A. Rossi performed the pseudovirus studies; AR and SS conducted the cell-cell fusion study; MGS and JFR designed the study; MGS, AR and SS wrote the manuscript. All the authors contributed to the interpretation of the data and approve the content of the manuscript. Funding Open access funding provided by Università degli Studi di Roma Tor Vergata within the CRUI-CARE Agreement. This research was supported by Romark Laboratories LC, Tampa, Florida, and by a grant from the Italian Ministry of University and Scientific Research (PRIN project N 2010PHT9NF-006).
Declarations Conflict of interest Financial support for this study was in part provided by Romark Laboratories LC, the company that owns the intellectual property rights related to nitazoxanide. JF Rossignol is an employee and stockholder of Romark..
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