Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57

Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no...

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Bibliographic Details
Published in:Scientific reports 2018-07, Vol.8 (1), p.10425-14, Article 10425
Main Authors: Piacentini, Sara, La Frazia, Simone, Riccio, Anna, Pedersen, Jens Z, Topai, Alessandra, Nicolotti, Orazio, Rossignol, Jean-Francois, Santoro, M Gabriella
Format: Article
Language:English
Subjects:
A549 Cells
Animals
Antimicrobial agents
Antiviral activity
Antiviral drugs
Binding Sites
Chemotherapy
Fusion protein
Genomes
Hepatitis
Humans
Infectivity
Influenza
Membrane fusion
Membrane proteins
Mumps
Oxidoreductases - metabolism
Parainfluenza
Paramyxoviridae - drug effects
Paramyxoviridae - physiology
Paramyxoviridae Infections - drug therapy
Paramyxoviridae Infections - prevention & control
Pathogens
Protein Disulfide-Isomerases - antagonists & inhibitors
Protein Disulfide-Isomerases - chemistry
Protein folding
Protein Folding - drug effects
Protein Transport
Respiratory syncytial virus
Ribonucleic acid
RNA
Rotavirus
Thiazoles - metabolism
Thiazoles - pharmacology
Thiol oxidoreductase
Tizoxanide
Viral Fusion Proteins - metabolism
Virus Replication - drug effects
Viruses
Zoonoses
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Summary:Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b' non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-28172-9