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

{ 'indexed': {'date-parts': [[2021, 12, 9]], 'date-time': '2021-12-09T08:11:14Z', 'timestamp': 1639037474248}, 'reference-count': 42, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2021, 3, 8]], 'date-time': '2021-03-08T00:00:00Z', 'timestamp': 1615161600000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2021, 3, 8]], 'date-time': '2021-03-08T00:00:00Z', 'timestamp': 1615161600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'short-container-title': ['Sci Rep'], 'published-print': {'date-parts': [[2021, 12]]}, '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\xa0µM, 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>', 'DOI': '10.1038/s41598-021-84782-w', 'type': 'journal-article', 'created': {'date-parts': [[2021, 3, 8]], 'date-time': '2021-03-08T11:03:05Z', 'timestamp': 1615201385000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 6, 'title': ['The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication'], 'prefix': '10.1038', 'volume': '11', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-5003-2081', 'authenticated-orcid': False, 'given': 'Madeline', 'family': 'Loffredo', 'sequence': 'first', 'affiliation': []}, {'given': 'Hector', 'family': 'Lucero', 'sequence': 'additional', 'affiliation': []}, {'given': 'Da-Yuan', 'family': 'Chen', 'sequence': 'additional', 'affiliation': []}, {'given': 'Aoife', 'family': 'O’Connell', 'sequence': 'additional', 'affiliation': []}, {'given': 'Simon', 'family': 'Bergqvist', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ahmad', 'family': 'Munawar', 'sequence': 'additional', 'affiliation': []}, {'given': 'Asanga', 'family': 'Bandara', 'sequence': 'additional', 'affiliation': []}, {'given': 'Steff', 'family': 'De Graef', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1360-0852', 'authenticated-orcid': False, 'given': 'Stephen D.', 'family': 'Weeks', 'sequence': 'additional', 'affiliation': []}, {'given': 'Florian', 'family': 'Douam', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mohsan', 'family': 'Saeed', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-9617-9460', 'authenticated-orcid': False, 'given': 'Ali H.', 'family': 'Munawar', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2021, 3, 8]]}, 'reference': [ { 'key': '84782_CR1', 'doi-asserted-by': 'publisher', 'first-page': '379', 'DOI': '10.1038/d41587-020-00003-1', 'volume': '38', 'author': 'C Harrison', 'year': '2020', 'unstructured': 'Harrison, C. 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