Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine

Abstract

Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. In this study, we describe the in vitro testing of CPZ against a SARS-CoV-2 isolate in monkey and human cells. We evidenced an antiviral activity against SARS-CoV-2 with an IC50 of ~10μM. Because of its high biodistribution in lung, saliva and brain, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine. This extrapolation is in line with our observations of a higher prevalence of symptomatic and severe forms of COVID-19 infections among health care professionals compared to patients in psychiatric wards. These preclinical findings support the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.

Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds

“…Terfenadine was withdrawn from the market in 1997 after 12 years due to evidence for cardiac toxicity via the binding to the hERG channel yet may still provide short term benefit as a SARS-CoV-2 prophylactic or acute treatment (Roy et al, 1996). Chlorpromazine was shown to block Epstein-Barr virus (Nemerow and Cooper, 1984) and influenza A virus (Krizanova et al, 1982) and very recently was found to be effective against SARS-CoV-2 in multiple in-vitro assays (Plaze et al, 2020), although we ruled it out early due to cellular toxicity.…”

The Large Action of Chlorpromazine: Translational and Transdisciplinary Considerations in the Face of COVID-19

“…In summary, CPZ as an anti-COVID-19 candidate is a fair illustration for repositioning the molecule as a treatment for COVID-19 with the findings of the two studies demonstrating in vitro activity against SARS-CoV-2 (Plaze et al, 2020b;Weston et al, 2020). These two pre-print studies demonstrate the in vitro activity of chlorpromazine against SARS-CoV-2 are crucial for proposing a repositioning.…”

“…They are not only repositioning themselves, but also offer repositioning of medication that they know very well. This is the case with the first known antipsychotic medication, CPZ (Plaze et al, 2020a;Plaze et al, 2020b;Stip, 2002;Stip, 2020). In 2020, a Canadian research letter (Stip, 2020) proposed the possibility that CPZ, a medication used in psychiatry for a long time, could potentially be used to counter COVID-19 (Nobile et al, 2020).…”

“…The proposal was based on an old antimicrobial and antiviral CPZ data that had been documented when studying the history of the introduction of CPZ in North America (Stip, 2015). The first use in psychiatry of CPZ was in France and interestingly it is from there too that a concrete statement for CPZ repositioning for COVID-19 has just emerged (Plaze et al, 2020a;Plaze et al, 2020b). Since then, controlled clinical trials are underway with well-supported hypotheses and a rigorous methodology (NCT 04366739, Repurposing of Chlorpromazine in reCoVery,France and NCT0434805,Egypt).…”

“…Recently, French researchers (Plaze et al, 2020a;Plaze et al, 2020b;Nobile et al, 2020) have also identified several other mechanisms and advantages of chlorpromazine (Zucker et al, 1990;Tarazona et al, 1995). For example, CPZ stimulates the production of IgM.…”