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

• Type of Material: Article
• Authors: Eloïne Bestion, Genosci Pharma; Keivan Zandi, Emory University; Sandrine Belouzard, Lille University; Julien Andreani, Aix-Marseille University; Hubert Lepidi, Aix-Marseille University; Marie Novello, Genosci Pharma; Clara Rouquairol, Genosci Pharma; Jean-Pierre Baudoin, Aix Marseille University; Madani Rachid, Genosci Pharma; Bernard La Scola, Aix Marseille Université; Jean-Louis Mege, Aix Marseille Université; Jean Dubuisson, Lille University; Raymond Schinazi, Emory University; Soraya Mezouar, Genosci Pharma; Philippe Halfon, Genosci Pharma
• Language: English
• Date: 2022-01-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/v14010132
• Title of Journal or Parent Work: VIRUSES-BASEL
• Volume: 14
• Issue: 1
• Grant/Funding Information: This research was funded in part by the Emory Center for AIDS Research (5P30-AI-50409 to RFS). The APC was funded by Genoscience Pharma. E.B. was also funded in part by ANRT, CIFRE no. 2018/0631.
• Keywords: Science & Technology; GNS561; COVID-19; Ezurpimtrostat; autophagy; Virology; SARS-CoV-2; TOXICITY; Life Sciences & Biomedicine; HYDROXYCHLOROQUINE; LC3; LYSOSOMES
• Research Categories: Health Sciences, Pharmacology

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.