GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition
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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.
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SciScore for 10.1101/2020.10.06.327635: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Six randomly selected microscopic fields of cells were acquired and collected by Zen 3.0 (Blue Edition) software (Zeiss). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Then, the coverslips were incubated in blocking buffer for 45 min at room temperature with antibodies against LC3-II (Sigma Aldrich, 1:200) LC3-IIsuggested: NoneThe secondary antibodies used to reveal LC3 and LAMP2 were Alexa 594-labeled anti-rabbit secondary antibody and Alexa 546-labeled anti-mouse secondary antibody (Invitrogen, USA), respectively. …SciScore for 10.1101/2020.10.06.327635: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Six randomly selected microscopic fields of cells were acquired and collected by Zen 3.0 (Blue Edition) software (Zeiss). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Then, the coverslips were incubated in blocking buffer for 45 min at room temperature with antibodies against LC3-II (Sigma Aldrich, 1:200) LC3-IIsuggested: NoneThe secondary antibodies used to reveal LC3 and LAMP2 were Alexa 594-labeled anti-rabbit secondary antibody and Alexa 546-labeled anti-mouse secondary antibody (Invitrogen, USA), respectively. LC3suggested: NoneLAMP2suggested: Noneanti-rabbitsuggested: Noneanti-mousesuggested: NoneExperimental Models: Cell Lines Sentences Resources Vero E6 cells cultured on coverslips were initially treated or not by a fluorescent analog of GNS561, GNS561G, for 2 hours and were then infected by SARS-CoV-2 (IHU-MI6, MOI 0.1). Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Six randomly selected microscopic fields of cells were acquired and collected by Zen 3.0 (Blue Edition) software (Zeiss). Zensuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT03316222 Recruiting Study of GNS561 in Patients With Liver Cancer NCT04333914 Recruiting Prospective Study in Patients With Advanced or Metastatic Ca… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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