The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication

DOI record: { "DOI": "10.1038/s41598-021-84782-w", "ISSN": [ "2045-2322" ], "URL": "http://dx.doi.org/10.1038/s41598-021-84782-w", "abstract": "<jats:title>Abstract</jats:title><jats:p>The lack of coronavirus-specific antiviral drugs has instigated multiple drug repurposing studies to redirect previously approved medicines for the treatment of SARS-CoV-2, the coronavirus behind the ongoing COVID-19 pandemic. A recent, large-scale, retrospective clinical study showed that famotidine, when administered at a high dose to hospitalized COVID-19 patients, reduced the rates of intubation and mortality. A separate, patient-reported study associated famotidine use with improvements in mild to moderate symptoms such as cough and shortness of breath. While a prospective, multi-center clinical study is ongoing, two parallel in silico studies have proposed one of the two SARS-CoV-2 proteases, 3CL<jats:sup>pro</jats:sup> or PL<jats:sup>pro</jats:sup>, as potential molecular targets of famotidine activity; however, this remains to be experimentally validated. In this report, we systematically analyzed the effect of famotidine on viral proteases and virus replication. Leveraging a series of biophysical and enzymatic assays, we show that famotidine neither binds with nor inhibits the functions of 3CL<jats:sup>pro</jats:sup> and PL<jats:sup>pro</jats:sup>. Similarly, no direct antiviral activity of famotidine was observed at concentrations of up to 200 µM, when tested against SARS-CoV-2 in two different cell lines, including a human cell line originating from lungs, a primary target of COVID-19. These results rule out famotidine as a direct-acting inhibitor of SARS-CoV-2 replication and warrant further investigation of its molecular mechanism of action in the context of COVID-19.</jats:p>", "alternative-id": [ "84782" ], "article-number": "5433", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "2 November 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "1 February 2021" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "8 March 2021" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "The authors declare no competing interests." } ], "author": [ { "ORCID": "http://orcid.org/0000-0002-5003-2081", "affiliation": [], "authenticated-orcid": false, "family": "Loffredo", "given": "Madeline", "sequence": "first" }, { "affiliation": [], "family": "Lucero", "given": "Hector", "sequence": "additional" }, { "affiliation": [], "family": "Chen", "given": "Da-Yuan", "sequence": "additional" }, { "affiliation": [], "family": "O’Connell", "given": "Aoife", "sequence": "additional" }, { "affiliation": [], "family": "Bergqvist", "given": "Simon", "sequence": "additional" }, { "affiliation": [], "family": "Munawar", "given": "Ahmad", "sequence": "additional" }, { "affiliation": [], "family": "Bandara", "given": "Asanga", "sequence": "additional" }, { "affiliation": [], "family": "De Graef", "given": "Steff", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-1360-0852", "affiliation": [], "authenticated-orcid": false, "family": "Weeks", "given": "Stephen D.", "sequence": "additional" }, { "affiliation": [], "family": "Douam", "given": "Florian", "sequence": "additional" }, { "affiliation": [], "family": "Saeed", "given": "Mohsan", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-9617-9460", "affiliation": [], "authenticated-orcid": false, "family": "Munawar", "given": "Ali H.", "sequence": "additional" } ], "container-title": [ "Scientific Reports" ], "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2021, 3, 8 ] ], "date-time": "2021-03-08T11:03:05Z", "timestamp": 1615201385000 }, "deposited": { "date-parts": [ [ 2021, 12, 2 ] ], "date-time": "2021-12-02T16:12:26Z", "timestamp": 1638461546000 }, "indexed": { "date-parts": [ [ 2021, 12, 9 ] ], "date-time": "2021-12-09T08:11:14Z", "timestamp": 1639037474248 }, "is-referenced-by-count": 6, "issn-type": [ { "type": "electronic", "value": "2045-2322" } ], "issue": "1", "issued": { "date-parts": [ [ 2021, 3, 8 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2021, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 3, 8 ] ], "date-time": "2021-03-08T00:00:00Z", "timestamp": 1615161600000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 3, 8 ] ], "date-time": "2021-03-08T00:00:00Z", "timestamp": 1615161600000 } } ], "link": [ { "URL": "http://www.nature.com/articles/s41598-021-84782-w.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "http://www.nature.com/articles/s41598-021-84782-w", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "http://www.nature.com/articles/s41598-021-84782-w.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2021, 3, 8 ] ] }, "published-online": { "date-parts": [ [ 2021, 3, 8 ] ] }, "published-print": { "date-parts": [ [ 2021, 12 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1038/d41587-020-00003-1", "author": "C Harrison", "doi-asserted-by": "publisher", "first-page": "379", "journal-title": "Nat. 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