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

• Published in: Scientific reports Vol. 11; no. 1; pp. 5433 - 9
• Main Authors: Loffredo, Madeline, Lucero, Hector, Chen, Da-Yuan, O’Connell, Aoife, Bergqvist, Simon, Munawar, Ahmad, Bandara, Asanga, De Graef, Steff, Weeks, Stephen D., Douam, Florian, Saeed, Mohsan, Munawar, Ali H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 692/4017; A549 Cells; Animals; Antiviral activity; Antiviral agents; Antiviral drugs; Cell lines; Chlorocebus aethiops; Coronaviridae; Coronaviruses; Cough; COVID-19; COVID-19 - virology; Famotidine; Famotidine - pharmacology; Humanities and Social Sciences; Humans; Intubation; multidisciplinary; Pandemics; Patients; Peptide Hydrolases - metabolism; Replication; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Vero Cells; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84782-w

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 pro or PL pro , 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 pro and PL pro . 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.