Antidepressant and Antipsychotic Drugs Reduce Viral Infection by SARS-CoV-2 and Fluoxetine Shows Antiviral Activity Against the Novel Variants in vitro.

Senem Merve Fred,Kalle Saksela,Suvi Kuivanen,Olli Vapalahti,Plinio Cabrera Casarotto,Hasan Ugurlu,Lev Levanov,Eero Castrén

doi:10.3389/fphar.2021.755600

Senem Merve Fred, Kalle Saksela + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2021.755600

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Abstract

Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our in vitro findings.

Highlights

Coronaviruses, members of the enveloped RNA virus family Coronaviridae (Lai & Cavanagh, 1997), are known to infect multiple species ranging from birds to mammals (To et al, 2013)
In order to confirm the activity of transmembrane protease/serine subfamily member 2 (TMPRSS2) in the HEK293TACE2-TMPRSS2 cell line, we treated the cells with different doses of camostat mesylate for 24 h and measured the level of viral infection
We examined the changes in mRNA level of Angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 by the viral infection combined with 24 h of fluoxetine (10 μM), clomipramine (10 μM), and chlorpromazine (5 μM) treatment (Supplementary Figure S4)

Summary

Introduction

Coronaviruses, members of the enveloped RNA virus family Coronaviridae (Lai & Cavanagh, 1997), are known to infect multiple species ranging from birds to mammals (To et al, 2013). In addition to four coronaviruses causing common colds, high level of pathogenicity of viruses from this family, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), were observed in epidemics that emerged in 2003 and 2012, respectively (Tang et al, 2015). The pandemic that started in December 2019 in Wuhan, China, caused by SARSCoV-2 infection, and the dramatic increase in the number of infected people and death due to COVID-19, has shifted the efforts of scientists towards investigating this virus more closely Severity of cases and high infectivity of the virus requires more attention and effort towards controlling the global epidemic and developing treatment options

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