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The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators

View ORCID ProfileKirill Gorshkov, Catherine Z. Chen, Robert Bostwick, Lynn Rasumussen, Miao Xu, Manisha Pradhan, Bruce Nguyen Tran, Wei Zhu, Khalida Shamim, Wenwei Huang, Xin Hu, View ORCID ProfileMin Shen, View ORCID ProfileCarleen Klumpp-Thomas, Zina Itkin, Paul Shinn, Anton Simeonov, Sam Michael, View ORCID ProfileMatthew D. Hall, Donald C. Lo, View ORCID ProfileWei Zheng
doi: https://doi.org/10.1101/2020.05.16.091520
Kirill Gorshkov
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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  • ORCID record for Kirill Gorshkov
  • For correspondence: kirill.gorshkov@nih.gov wzheng@mail.nih.gov
Catherine Z. Chen
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Robert Bostwick
2Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205
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Lynn Rasumussen
2Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205
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Miao Xu
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Manisha Pradhan
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Bruce Nguyen Tran
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Wei Zhu
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Khalida Shamim
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Wenwei Huang
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Xin Hu
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Min Shen
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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  • ORCID record for Min Shen
Carleen Klumpp-Thomas
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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  • ORCID record for Carleen Klumpp-Thomas
Zina Itkin
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Paul Shinn
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Anton Simeonov
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Sam Michael
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Matthew D. Hall
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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  • ORCID record for Matthew D. Hall
Donald C. Lo
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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Wei Zheng
1National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850
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  • ORCID record for Wei Zheng
  • For correspondence: kirill.gorshkov@nih.gov wzheng@mail.nih.gov
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Abstract

SARS-CoV-2 is a new type of coronavirus capable of rapid transmission and causing severe clinical symptoms; much of which has unknown biological etiology. It has prompted researchers to rapidly mobilize their efforts towards identifying and developing anti-viral therapeutics and vaccines. Discovering and understanding the virus’ pathways of infection, host-protein interactions, and cytopathic effects will greatly aid in the design of new therapeutics to treat COVID-19. While it is known that chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including inhibiting autophagy, there are also dose-limiting toxicities in patients that make clearly establishing their potential mechanisms-of-action problematic. Therefore, we evaluated a range of other autophagy modulators to identify an alternative autophagy-based drug repurposing opportunity. In this work, we found that 6 of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero-E6 cells with EC50 values ranging from 2.0 to 13 µM and selectivity indices ranging from 1.5 to >10-fold. Immunofluorescence staining for LC3B and LysoTracker dye staining assays in several cell lines indicated their potency and efficacy for inhibiting autophagy correlated with the measurements in the SARS-CoV-2 cytopathic effect assay. Our data suggest that autophagy pathways could be targeted to combat SARS-CoV-2 infections and become an important component of drug combination therapies to improve the treatment outcomes for COVID-19.

One Sentence Summary Blocking SARS-CoV-2 cytopathic effects with selective autophagy inhibitors underlying the clinical benefits of chloroquine and hydroxychloroquine.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 21, 2020.
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The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators
Kirill Gorshkov, Catherine Z. Chen, Robert Bostwick, Lynn Rasumussen, Miao Xu, Manisha Pradhan, Bruce Nguyen Tran, Wei Zhu, Khalida Shamim, Wenwei Huang, Xin Hu, Min Shen, Carleen Klumpp-Thomas, Zina Itkin, Paul Shinn, Anton Simeonov, Sam Michael, Matthew D. Hall, Donald C. Lo, Wei Zheng
bioRxiv 2020.05.16.091520; doi: https://doi.org/10.1101/2020.05.16.091520
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The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators
Kirill Gorshkov, Catherine Z. Chen, Robert Bostwick, Lynn Rasumussen, Miao Xu, Manisha Pradhan, Bruce Nguyen Tran, Wei Zhu, Khalida Shamim, Wenwei Huang, Xin Hu, Min Shen, Carleen Klumpp-Thomas, Zina Itkin, Paul Shinn, Anton Simeonov, Sam Michael, Matthew D. Hall, Donald C. Lo, Wei Zheng
bioRxiv 2020.05.16.091520; doi: https://doi.org/10.1101/2020.05.16.091520

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