Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

DOI record: { "DOI": "10.1007/s00018-022-04246-w", "ISSN": [ "1420-682X", "1420-9071" ], "URL": "http://dx.doi.org/10.1007/s00018-022-04246-w", "abstract": "<jats:title>Abstract</jats:title><jats:p>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 nitazoxanide-induced 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.\n</jats:p>", "alternative-id": [ "4246" ], "article-number": "227", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "5 January 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Revised", "name": "revised", "order": 2, "value": "3 March 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 3, "value": "11 March 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 4, "value": "7 April 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Change Date", "name": "change_date", "order": 5, "value": "30 July 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Change Type", "name": "change_type", "order": 6, "value": "Update" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Change Details", "name": "change_details", "order": 7, "value": "Missing Open Access funding information has been added in the Funding Note" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Conflict of interest", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "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." }, { "group": { "label": "Ethics approval", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "Not applicable." }, { "group": { "label": "Consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 4, "value": "Not applicable." }, { "group": { "label": "Consent to publish", "name": "EthicsHeading" }, "name": "Ethics", "order": 5, "value": "Not applicable." } ], "author": [ { "affiliation": [], "family": "Riccio", "given": "Anna", "sequence": "first" }, { "affiliation": [], "family": "Santopolo", "given": "Silvia", "sequence": "additional" }, { "affiliation": [], "family": "Rossi", "given": "Antonio", "sequence": "additional" }, { "affiliation": [], "family": "Piacentini", "given": "Sara", "sequence": "additional" }, { "affiliation": [], "family": "Rossignol", "given": "Jean-Francois", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-1432-4949", "affiliation": [], "authenticated-orcid": false, "family": "Santoro", "given": "M. 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