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.
Highlights
In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged to rapidly spread worldwide and was qualified as a pandemic [1]
Regarding GNS561-specific effects on autophagy in the Vero E6 cell model, we performed a protein expression analysis focused on the light chain 3 phosphatidylethanolamine conjugate (LC3-II) and p62 protein levels, two well-known autophagy markers [20]
Normalized LC3-II protein expression increased in a dosedependent manner, without a further increase when bafilomycin A1 (Baf A1) treatment was added at the highest dose (Figure 1A), reflecting the accumulation of autophagosomes in cells
Summary
In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged to rapidly spread worldwide and was qualified as a pandemic [1]. As of October 2021, more than 280 million confirmed cases, including over 5,000,000 deaths, have been reported (World Health Organization data). The SARS-CoV-2-resulting disease, coronavirus disease 2019 (COVID-19), leads to a range of symptoms from a mild fever to acute respiratory distress syndrome, classifying this disease into several clinical categories, including asymptomatic, mild, moderate, severe, and critical infection [2]. Attributed EUA was addressed to already hospitalized patients, aiming to prevent critical status and deaths. Available treatments that enable the prevention of general health status deterioration for less-severe patients are an imperative to hamper an actual sanitary crisis (who.int)
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