2. Academic Validation
  3. GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition

GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition

  • Viruses. 2022 Jan 12;14(1):132. doi: 10.3390/v14010132.
Eloïne Bestion 1 2 3,  Keivan Zandi 4,  Sandrine Belouzard 5,  Julien Andreani 2 3,  Hubert Lepidi 6,  Marie Novello 1,  Clara Rouquairol 1,  Jean-Pierre Baudoin 2 3,  Madani Rachid 1,  Bernard La Scola 2 3,  Jean-Louis Mege 2 3,  Jean Dubuisson 5,  Raymond F Schinazi 4,  Soraya Mezouar 1 2 3,  Philippe Halfon 1
Affiliations

Affiliations

  • 1 Genoscience Pharma, 13006 Marseille, France.
  • 2 Institut de Recherche Pour le Développement, Aix-Marseille University, Assitance Publique-Hopitaux de Marseille, Microbe, Phylogeny and Infection, 13005 Marseille, France.
  • 3 Institut Hospitalo-Universitaire Méditerranée Infection, Aix-Marseille University, 13005 Marseille, France.
  • 4 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 5 Lille University, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille (CIIL), INSERM U 1019-UMR 9017-UMR 8204, 59019 Lille, France.
  • 6 Department of Pathology, La Timone Hospital, Aix-Marseille Université, 13005 Marseille, France.
PMID: 35062337 DOI: 10.3390/v14010132
Abstract

Since December 2019, SARS-CoV-2 has spread quickly worldwide, leading to more than 280 million confirmed cases, including over 5,000,000 deaths. Interestingly, coronaviruses were found to subvert and hijack autophagic process to allow their viral replication. Autophagy-modulating compounds thus rapidly emerged as an attractive strategy to fight SARS-CoV-2 Infection, including the well-known chloroquine (CQ). Here, we investigated the Antiviral activity and associated mechanism of GNS561/Ezurpimtrostat, a small lysosomotropic molecule inhibitor of late-stage Autophagy. Interestingly, GNS561 exhibited Antiviral activity of 6-40 nM depending on the viral strain considered, currently positioning it as the most powerful molecule investigated in SARS-CoV-2 Infection. We then showed that GNS561 was located in lysosome-associated-membrane-protein-2-positive (LAMP2-positive) lysosomes, together with SARS-CoV-2. Moreover, GNS561 increased LC3-II spot size and caused the accumulation of autophagic vacuoles and the presence of multilamellar bodies, suggesting that GNS561 disrupted the Autophagy mechanism. To confirm our findings, we used the K18-hACE2 mouse model and highlighted that GNS561 treatment led to a decline in SARS-CoV-2 virions in the lungs associated with a disruption of the Autophagy pathway. Overall, our study highlights GNS561 as a powerful drug in the treatment of SARS-CoV-2 Infection and supports the hypothesis that Autophagy blockers could be an alternative strategy for COVID-19.

Keywords

COVID-19; GNS561/Ezurpimtrostat; LC3; SARS-CoV-2; autophagy.

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