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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\n                    <jats:sup>pro<\/jats:sup>\n                    or PL\n                    <jats:sup>pro<\/jats:sup>\n                    , 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\n                    <jats:sup>pro<\/jats:sup>\n                    and PL\n                    <jats:sup>pro<\/jats:sup>\n                    . Similarly, no direct antiviral activity of famotidine was observed at concentrations of up to 200\u00a0\u00b5M, 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-84782-w","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T06:03:05Z","timestamp":1615183385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The in-vitro effect of famotidine on SARS-CoV-2 proteases and virus replication"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5003-2081","authenticated-orcid":false,"given":"Madeline","family":"Loffredo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector","family":"Lucero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-Yuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aoife","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Bergqvist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad","family":"Munawar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asanga","family":"Bandara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steff","family":"De Graef","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-0852","authenticated-orcid":false,"given":"Stephen D.","family":"Weeks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Douam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohsan","family":"Saeed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9617-9460","authenticated-orcid":false,"given":"Ali H.","family":"Munawar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"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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