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Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by the broad-spectrum anti-infective drug nitazoxanide

Anna Riccio, Silvia Santopolo, Antonio Rossi, Sara Piacentini, Jean-Francois Rossignol, View ORCID ProfileM. Gabriella Santoro
doi: https://doi.org/10.1101/2021.04.12.439201
Anna Riccio
1Department of Biology, University of Rome Tor Vergata, Rome, Italy
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Silvia Santopolo
1Department of Biology, University of Rome Tor Vergata, Rome, Italy
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Antonio Rossi
2Institute of Translational Pharmacology, CNR, Rome, Italy
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Sara Piacentini
1Department of Biology, University of Rome Tor Vergata, Rome, Italy
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Jean-Francois Rossignol
3Romark Institute of Medical Research, Tampa, Florida, USA
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M. Gabriella Santoro
1Department of Biology, University of Rome Tor Vergata, Rome, Italy
2Institute of Translational Pharmacology, CNR, Rome, Italy
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  • ORCID record for M. Gabriella Santoro
  • For correspondence: santoro@uniroma2.it
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ABSTRACT

The emergence of the highly-pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 (coronavirus disease-2019), has caused an unprecedented global health crisis, as well as societal and economic disruption. The SARS-CoV-2 spike (S), a surface-anchored trimeric class-I fusion glycoprotein essential for entry into host cells, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of several SARS-CoV-2 spike variants that facilitate virus spread and may affect the efficacy of recently developed vaccines, creates great concern and highlights the importance of identifying antiviral drugs to reduce SARS-CoV-2-related morbidity and mortality. Nitazoxanide, a thiazolide originally developed as an antiprotozoal agent with recognized broad-spectrum antiviral activity in-vitro and in clinical studies, was recently shown to be effective against several coronaviruses, including SARS-CoV-2. Using biochemical and pseudovirus entry assays, we now demonstrate that nitazoxanide interferes with the SARS-CoV-2 spike biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage, and hindering its fusion activity in human cells. Besides membrane fusion during virus entry, SARS-CoV-2 S-proteins in infected cells can also trigger receptor-dependent formation of syncytia, observed in-vitro and in COVID-19 patients tissues, facilitating viral dissemination between cells and possibly promoting immune evasion. Utilizing two different quantitative cell-cell fusion assays, we show that nitazoxanide is effective in inhibiting syncytia formation mediated by different SARS-CoV-2 spike variants in human lung, liver and intestinal cells. The results suggest that nitazoxanide may represent a useful tool in the fight against COVID-19 infections, inhibiting SARS-CoV-2 replication and preventing spike-mediated syncytia formation.

Competing Interest Statement

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 Laboratories, LC.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 12, 2021.
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Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by the broad-spectrum anti-infective drug nitazoxanide
Anna Riccio, Silvia Santopolo, Antonio Rossi, Sara Piacentini, Jean-Francois Rossignol, M. Gabriella Santoro
bioRxiv 2021.04.12.439201; doi: https://doi.org/10.1101/2021.04.12.439201
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Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by the broad-spectrum anti-infective drug nitazoxanide
Anna Riccio, Silvia Santopolo, Antonio Rossi, Sara Piacentini, Jean-Francois Rossignol, M. Gabriella Santoro
bioRxiv 2021.04.12.439201; doi: https://doi.org/10.1101/2021.04.12.439201

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