PT - JOURNAL ARTICLE AU - Reza Nejat AU - Ahmad Shahir Sadr AU - Brendan T. Freitas AU - Jackelyn Crabtree AU - Scott D. Pegan AU - Ralph A. Tripp AU - David J. Najafi TI - Losartan promotes cell survival following SARS-CoV-2 infection <em>in vitro</em> AID - 10.1101/2020.12.27.424507 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.12.27.424507 4099 - http://biorxiv.org/content/early/2020/12/28/2020.12.27.424507.short 4100 - http://biorxiv.org/content/early/2020/12/28/2020.12.27.424507.full AB - Introduction Coronavirus disease 2019 (COVID-19) can be associated with mortality and high morbidity worldwide. There is an extensive effort to control infection and disease caused by SARS-CoV-2. This study addressed the hypothesis that angiotensin II type I receptor blocker, Losartan, may restrict pathogenesis caused by SARS-CoV-2 by decreasing viral-induced cytopathological changes by blocking angiotensin II type 1 receptor (AT1R), thus reducing the affinity of the virus for ACE2, and inhibiting papain-like protease of the virus.Method Losartan inhibitory effect on deubiquitination and deISGylation properties of papain-like protease was investigated using a fluorescence method and gel shift analysis determining its inhibitory effects.The inhibitory effect of Losartan on SARS-CoV-2 cell replication was investigated both when losartan was added to the cell culture 1 hour before (pre-infection group) and 1 hour after (post-infection group) SARS-CoV-2 infection of Vero E6 cells.Results Losartan treatment of Vero E6 cells prior to and after SARS-CoV-2 infection reduced SARS-CoV-2 replication by 80% and 70% respectively. Losartan was not a strong deubiquitinase and deISGylase inhibitor of PLpro.Conclusion Losartan added pre- and post-infection to the Vero E6 cell culture significantly prevents cell destruction and replication by SARS-CoV2. Losartan has low side-effects, is readily available, and can be produced at high levels globally, all features of a promising drug in treatment of COVID-19 if validated by clinical trials.Competing Interest StatementThe authors have declared no competing interest.ACEAngiotensin-Converting EnzymeACE2Angiotensin-Converting Enzyme 2AMCC-terminal 7-amido-4-methylcoumarinAng IAngiotensin IAng IIAngiotensin IIAng (1-7)Angiotensin 1-7Ang (1-9)Angiotensin 1-9ARBangiotensin receptor blockersARDSacute respiratory distress syndromeAT1RAngiotensin II type 1 receptorAT2RAngiotensin II type 2 receptorBSAbovine serum albuminCoVcoronavirusCOVID-19coronavirus disease 2019;DMSOdimethyl sulfoxideDUBdeubiquitinaseGRL-06175-amino-2-methyl-NbenzamideIL-6interleukin-6ISG15interferon-stimulated gene product 15MDmolecular dynamicMERS-CoVMiddle East Respiratory SyndromeNPnuclear proteinNSPnonstructural proteinsORF1a/ORF1bopen reading framesPLPpapain-like proteasePLpropapain-like proteaseproISG15precursor ISG15PRRPattern-Recognition ReceptorRASrenin-angiotensin systemRBDreceptor binding domainSARS-CoV-2severe acute respiratory syndrome coronavirus 2TLRToll-like receptorTristris(hydroxymethyl)-aminomethaneUbubiquitinpoly ubpolyubiquitinUIMubiquitin interacting motif