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

Marion Plaze (1, 2) , David Attali (1, 2, 3) , Matthieu Prot (4) , Anne-Cécile Petit (1, 5) , Michael Blatzer (5) , Fabien Vinckier (1, 2) , Laurine Levillayer (6) , Jeanne Chiaravalli (7) , Florent Perin-Dureau (8) , Arnaud Cachia (9, 10) , Gérard Friedlander (2) , Fabrice Chrétien (2, 5, 1) , Etienne Simon-Loriere (4) , Raphaël Gaillard (1, 2, 5)

1 GHU Paris Psychiatrie et Neurosciences
2 UPCité - Université Paris Cité
3 PhysMed Paris - Physique pour la médecine
4 Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses
5 Neuropathologie expérimentale / Experimental neuropathology
6 Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases
7 PF-CCB - Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform
8 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
9 LaPsyDÉ - UMR 8240 - Laboratoire de psychologie du développement et de l'éducation de l'enfant
10 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris

IntroductionUrgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells.Materials and methodsMonkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells.ResultsCPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 µM, half maximal cytotoxic concentration (CC50) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 µM, CC50 of 23.1 µM and SI of 2.04.DiscussionAlthough the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19.ConclusionsThese preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.

Mots clés: COVID-19; Chlorpromazine; Human cells; Repurposing of molecules; SARS-CoV-2

Domaines: Sciences du Vivant [q-bio]

Marion Plaze, David Attali, Matthieu Prot, Anne-Cécile Petit, Michael Blatzer, et al.. Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine. International Journal of Antimicrobial Agents, 2021, 57 (3), pp.106274. ⟨10.1016/j.ijantimicag.2020.106274⟩. ⟨pasteur-03277133⟩