Mechanisms of SARS-CoV-2 entry : host-virus relationship at primary site of infection and therapeutic repositioning
Mécanismes d’entrée de SARS-CoV-2 : relation hôte-virus au site de primo-infection et repositionnement thérapeutique
Résumé
The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a new member of the Orthocoronavirinae subfamily, emerged in 2019 in China and rapidly spread worldwide causing a pandemic. Considerable efforts have been done to develop effective vaccines against SARS-CoV-2 in record time. However, the emergence of new variants shows the fragility of a system only based on vaccines and highlights the need for preventive and curative treatments. Endosome/lysosome are key cell organelles involved in the Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) entry. Cationic amphiphilic drugs (CADs) are characterized by a hydrophobic aromatic ring and a hydrophilic side chain containing an ionizable amine functional group and are known to impair lysosomal functions. The objective of this study was to explore 8 FDA-approved CADs against SARS-CoV-2 replication in vitro and ex vivo.5/8 CADs (loratadine, desloratadine, chlorpromazine, imipramine and amitriptyline), all containing a tricyclic ring skeleton, significantly reduced SARS-CoV-2 RNA production with a decrease greater than 2-log in Vero-E6 cells. Desloratadine had the best reduction rate of SARS-CoV-2 RNA production, with a decrease of 6673-fold and had the best therapeutic index (23.3, EC50: 0.7 ± 0.4µM, CC50: 15.5 ± 1.1µM). Desloratadine also decreased viral RNA production of HCoV-229E and HCoV-OC43. A decrease of SARS-CoV-2 infected cells was only observed when desloratadine was present during the first two hours of infection, suggesting that desloratadine targets an early step of SARS-CoV-2 lifecycle in Vero-E6 cells. Desloratadine inhibited SARS-CoV 2 infection in Vero-E6 cells but not in Calu-3 cells, suggesting that this CAD could block SARS-CoV-2 entry via the endosomal route. The time-course antiviral effect of desloratadine was evaluated in HNECs, with a maximal decrease of viral RNA production after 72 hours of treatment.Desloratadine may provide a substantial contribution to systemic therapy of COVID-19, by targeting an early step of SARS-CoV-2 lifecycle, i.e., entry via the endosomal route. Desloratadine has the advantage of being a well-tolerated drug with no major side effects. Randomized clinical trials are needed to evaluate the specific antiviral activity of desloratadine against SARS-CoV-2 or other coronaviruses
Un projet de repositionnement thérapeutique a été développé avec le Prof. S. Jamain (Institut Mondor de Recherche Biomédicale, Equipe 15), basé sur l’absence de patients COVID-19 au sein des unités psychiatriques. Parmi les 18 molécules « FDA-approved » couramment prescrites en psychiatrie (antibiotiques, antidépresseurs, antipsychotiques et antihistaminiques), 10/18 possèdent une activité antivirale in vitro, et appartiennent à la famille des CADs (« Cationic Amphiphilic Drugs) (Villoutreix, 2020). Le potentiel anti-SARS-CoV-2 de 16 molécules CADs a alors été évalué en VERO-E6 et nous avons observé une diminution importante de la réplication virale pour 7/16 de ces molécules à 10 M. Dans cette lignée cellulaire, toutes les EC50 et CC50 ont été calculées et une molécule présentant le meilleur index thérapeutique a été sélectionnée. Des expériences de « TOAA » en VERO-E6 montrent que cette molécule cible l’entrée de SARS-CoV-2. L’absence d’activité antivirale dans la lignée Calu-3 suggère une inhibition de l’entrée du virus par la voie endosomale.
Origine | Version validée par le jury (STAR) |
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