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

Autor: Michael Blatzer, Raphaël Gaillard, Gérard Friedlander, Fabien Vinckier, David Attali, Etienne Simon-Loriere, Jeanne Chiaravalli, Anne-Cécile Petit, Laurine Levillayer, Matthieu Prot, Marion Plaze, Fabrice Chrétien, Florent Perin-Dureau, Arnaud Cachia
Přispěvatelé: CCSD, Accord Elsevier, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, GHU Paris Psychiatrie et Neurosciences, Université Paris Cité (UPCité), Physique pour la médecine (PhysMed Paris), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Laboratoire de psychologie du développement et de l'éducation de l'enfant (LaPsyDÉ - UMR 8240), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This study has received funding from Institut Pasteur (covid-therap), from the French Government's Investissement d'Avenir programme and as a recognition as a Laboratoire d'Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (Grant No. ANR-10-LABX-62-IBEID). ESL acknowledges funding from the INCEPTION programme (Investissements d'Avenir Grant ANR-16-CONV-0005)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Université de Paris (UP), Physique pour la médecine (UMR 8063, U1273), Institut Pasteur [Paris], Institut Pasteur [Paris]-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Saliva
viruses
[SDV]Life Sciences [q-bio]
Repurposing of molecules
Pharmacology
Virus Replication
0302 clinical medicine
MESH: Chlorocebus aethiops
Chlorocebus aethiops
Medicine
MESH: COVID-19
Pharmacology (medical)
Tissue Distribution
MESH: Animals
030212 general & internal medicine
Chlorpromazine
media_common
virus diseases
General Medicine
respiratory system
Human cells
3. Good health
[SDV] Life Sciences [q-bio]
Infectious Diseases
MESH: Drug Repositioning
medicine.drug
Microbiology (medical)
Drug
MESH: Antiviral Agents
media_common.quotation_subject
030106 microbiology
MESH: Vero Cells
Endocytosis
Antiviral Agents
Article
Cell Line
03 medical and health sciences
Distribution (pharmacology)
Animals
Humans
MESH: SARS-CoV-2
Viability assay
MESH: Tissue Distribution
IC50
Vero Cells
MESH: Humans
business.industry
SARS-CoV-2
MESH: Virus Replication
Drug Repositioning
COVID-19
MESH: Chlorpromazine
In vitro
respiratory tract diseases
COVID-19 Drug Treatment
MESH: Cell Line
A549 Cells
MESH: A549 Cells
business
Zdroj: International Journal of Antimicrobial Agents
International Journal of Antimicrobial Agents, 2021, 57 (3), pp.106274. ⟨10.1016/j.ijantimicag.2020.106274⟩
International Journal of Antimicrobial Agents, Elsevier, 2021, 57 (3), pp.106274. ⟨10.1016/j.ijantimicag.2020.106274⟩
ISSN: 0924-8579
DOI: 10.1016/j.ijantimicag.2020.106274
Popis: Highlights • Chlorpromazine, an FDA-approved drug, inhibits clathrin-mediated endocytosis • CPZ acts as an antiviral against SARS-CoV-1 and MERS-CoV • We evidenced antiviral activity of CPZ against SARS-CoV-2 in monkey and human cells • Because of CPZ high distribution in lungs, CPZ IC50 may translate in clinical routine • CPZ brain distribution could be of high interest for neurological forms of COVID-19
Introduction 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. The aim of this in vitro study was to test CPZ against a SARS-CoV-2 isolate in monkey and human cells. Material and methods Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in presence of different concentrations of CPZ. Supernatants were harvested at day 2 and analysed by RT-qPCR for the presence of SARS-CoV-2 RNA. Cell viability was assessed on non-infected cells. Results We evidenced an antiviral activity of CPZ against SARS-CoV-2 in monkey VeroE6 cells with an IC50 of 8.2 µM, a CC50 of 13.5µM and a SI of 1.65. In human A549-ACE2 cells, CPZ was also associated with an anti-SARS-CoV-2 activity, with an IC50 of 11.3 µM, a CC50 of 23.1 µM and a SI of 2.04. Discussion Even though the measured SI are low, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine because of CPZ high biodistribution in lungs and in saliva. Also, CPZ brain distribution could be of high interest for treating or preventing the neurological and psychiatric forms of COVID-19. Conclusions These preclinical findings support clinical investigation of the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.
Databáze: OpenAIRE
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