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GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition

Philippe Halfon, Eloïne Bestion, Keivan Zandi, Julien Andreani, Jean-Pierre Baudoin, Bernard La Scola, Jean-Louis Mege, Soraya Mezouar, Raymond F. Schinazi
doi: https://doi.org/10.1101/2020.10.06.327635
Philippe Halfon
1Genoscience Pharma, Marseille, France
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  • For correspondence: phalfon@genosciencepharma.com
Eloïne Bestion
1Genoscience Pharma, Marseille, France
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Keivan Zandi
3Emory University and Children’s Healthcare of Atlanta, Laboratory of Biochemical Pharmacology, Atlanta, GA 30322, USA
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Julien Andreani
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Jean-Pierre Baudoin
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Bernard La Scola
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Jean-Louis Mege
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Soraya Mezouar
1Genoscience Pharma, Marseille, France
2IRD, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, Marseille, France
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Raymond F. Schinazi
3Emory University and Children’s Healthcare of Atlanta, Laboratory of Biochemical Pharmacology, Atlanta, GA 30322, USA
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Abstract

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection.

Competing Interest Statement

P.H., E.B. and S.M. are Genoscience Pharma Employees.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 06, 2020.
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GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition
Philippe Halfon, Eloïne Bestion, Keivan Zandi, Julien Andreani, Jean-Pierre Baudoin, Bernard La Scola, Jean-Louis Mege, Soraya Mezouar, Raymond F. Schinazi
bioRxiv 2020.10.06.327635; doi: https://doi.org/10.1101/2020.10.06.327635
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GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition
Philippe Halfon, Eloïne Bestion, Keivan Zandi, Julien Andreani, Jean-Pierre Baudoin, Bernard La Scola, Jean-Louis Mege, Soraya Mezouar, Raymond F. Schinazi
bioRxiv 2020.10.06.327635; doi: https://doi.org/10.1101/2020.10.06.327635

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