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Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds

Daisy A. Hoagland, Daniel J.B. Clarke, Rasmus Møller, Yuling Han, Liuliu Yang, Megan L. Wojciechowicz, Alexander Lachmann, Kasopefoluwa Y. Oguntuyo, Christian Stevens, Benhur Lee, Shuibing Chen, Avi Ma’ayan, Benjamin R tenOever
doi: https://doi.org/10.1101/2020.07.12.199687
Daisy A. Hoagland
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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Daniel J.B. Clarke
2Department of Pharmacological Sciences; Mount Sinai Center for Bioinformatics; Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA
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Rasmus Møller
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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Yuling Han
3Department of Surgery, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA
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Liuliu Yang
3Department of Surgery, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA
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Megan L. Wojciechowicz
2Department of Pharmacological Sciences; Mount Sinai Center for Bioinformatics; Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA
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Alexander Lachmann
2Department of Pharmacological Sciences; Mount Sinai Center for Bioinformatics; Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA
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Kasopefoluwa Y. Oguntuyo
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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Christian Stevens
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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Benhur Lee
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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Shuibing Chen
3Department of Surgery, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA
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Avi Ma’ayan
2Department of Pharmacological Sciences; Mount Sinai Center for Bioinformatics; Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA
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  • For correspondence: benjamin.tenOever@mssm.edu avi.maayan@mssm.edu
Benjamin R tenOever
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA
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  • For correspondence: benjamin.tenOever@mssm.edu avi.maayan@mssm.edu
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Abstract

To interfere with the biology of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, we focused on restoring the transcriptional response induced by infection. Utilizing expression patterns of SARS-CoV-2-infected cells, we identified a region in gene expression space that was unique to virus infection and inversely proportional to the transcriptional footprint of known compounds characterized in the Library of Integrated Network-based Cellular Signatures. Here we demonstrate the successful identification of compounds that display efficacy in blocking SARS-CoV-2 replication based on their ability to counteract the virus-induced transcriptional landscape. These compounds were found to potently reduce viral load despite having no impact on viral entry or modulation of the host antiviral response in the absence of virus. RNA-Seq profiling implicated the induction of the cholesterol biosynthesis pathway as the underlying mechanism of inhibition and suggested that targeting this aspect of host biology may significantly reduce SARS-CoV-2 viral load.

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 July 13, 2020.
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Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds
Daisy A. Hoagland, Daniel J.B. Clarke, Rasmus Møller, Yuling Han, Liuliu Yang, Megan L. Wojciechowicz, Alexander Lachmann, Kasopefoluwa Y. Oguntuyo, Christian Stevens, Benhur Lee, Shuibing Chen, Avi Ma’ayan, Benjamin R tenOever
bioRxiv 2020.07.12.199687; doi: https://doi.org/10.1101/2020.07.12.199687
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Modulating the transcriptional landscape of SARS-CoV-2 as an effective method for developing antiviral compounds
Daisy A. Hoagland, Daniel J.B. Clarke, Rasmus Møller, Yuling Han, Liuliu Yang, Megan L. Wojciechowicz, Alexander Lachmann, Kasopefoluwa Y. Oguntuyo, Christian Stevens, Benhur Lee, Shuibing Chen, Avi Ma’ayan, Benjamin R tenOever
bioRxiv 2020.07.12.199687; doi: https://doi.org/10.1101/2020.07.12.199687

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