Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19

View ORCID ProfileCarmen Mirabelli, View ORCID ProfileJesse W. Wotring, View ORCID ProfileCharles J. Zhang, View ORCID ProfileSean M. McCarty, View ORCID ProfileReid Fursmidt, View ORCID ProfileTristan Frum, View ORCID ProfileNamrata S. Kadambi, View ORCID ProfileAnya T. Amin, View ORCID ProfileTeresa R. O’Meara, Carla D. Pretto, View ORCID ProfileJason R. Spence, Jessie Huang, Konstantinos D. Alysandratos, View ORCID ProfileDarrell N. Kotton, View ORCID ProfileSamuel K. Handelman, View ORCID ProfileChristiane E. Wobus, View ORCID ProfileKevin J. Weatherwax, View ORCID ProfileGeorge A. Mashour, View ORCID ProfileMatthew J. O’Meara, View ORCID ProfileJonathan Z. Sexton
doi: https://doi.org/10.1101/2020.05.27.117184
Carmen Mirabelli
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Carmen Mirabelli
Jesse W. Wotring
2Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jesse W. Wotring
Charles J. Zhang
2Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Charles J. Zhang
Sean M. McCarty
2Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sean M. McCarty
Reid Fursmidt
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
4U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Reid Fursmidt
Tristan Frum
5Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Tristan Frum
Namrata S. Kadambi
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Namrata S. Kadambi
Anya T. Amin
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anya T. Amin
Teresa R. O’Meara
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Teresa R. O’Meara
Carla D. Pretto
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason R. Spence
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
5Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jason R. Spence
Jessie Huang
6Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA
7The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Konstantinos D. Alysandratos
6Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA
7The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Darrell N. Kotton
6Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA
7The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Darrell N. Kotton
Samuel K. Handelman
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
4U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Samuel K. Handelman
Christiane E. Wobus
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Christiane E. Wobus
Kevin J. Weatherwax
4U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
8Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA
9College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kevin J. Weatherwax
George A. Mashour
4U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
8Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA
10Department of Anesthesiology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for George A. Mashour
Matthew J. O’Meara
11Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew J. O’Meara
Jonathan Z. Sexton
2Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
3Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA
4U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
8Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jonathan Z. Sexton
  • For correspondence: jzsexton@umich.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10-15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds with in vitro antiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein classically found in secretory fluids, including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.

IMPORTANCE Since its emergence in China in December 2019, SARS-CoV-2 has caused a global pandemic. Repurposing of FDA-approved drugs is a promising strategy for identifying rapidly deployable treatments for COVID-19. Herein, we developed a pipeline for quantitative high-throughput image-based screening of SARS-CoV-2 infection in human cells that led to the identification of several FDA-approved drugs and clinical candidates with in vitro antiviral activity.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵‡ Co-Senior Authors

  • Conflicts of interest The authors declare no conflicts of interest.

  • We have added additional virology experiments to validate mechanism of action of active compounds including lactoferrin confirmation as a viral entry inhibitor. We have also added confirmation of efficacy in three cell lines: Vero E6, Caco2 and LNCaP.

  • Abbreviations

    MOI
    multiplicity of infection
    COVID-19
    Coronavirus Disease-2019
    MOA
    mechanism of action
    iAEC2
    induced pluripotent stem cell (iPSC)-derived alveolar epithelial type 2 cells
  • 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.
    Back to top
    PreviousNext
    Posted December 07, 2020.
    Download PDF
    Email

    Thank you for your interest in spreading the word about bioRxiv.

    NOTE: Your email address is requested solely to identify you as the sender of this article.

    Enter multiple addresses on separate lines or separate them with commas.
    Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19
    (Your Name) has forwarded a page to you from bioRxiv
    (Your Name) thought you would like to see this page from the bioRxiv website.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Share
    Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19
    Carmen Mirabelli, Jesse W. Wotring, Charles J. Zhang, Sean M. McCarty, Reid Fursmidt, Tristan Frum, Namrata S. Kadambi, Anya T. Amin, Teresa R. O’Meara, Carla D. Pretto, Jason R. Spence, Jessie Huang, Konstantinos D. Alysandratos, Darrell N. Kotton, Samuel K. Handelman, Christiane E. Wobus, Kevin J. Weatherwax, George A. Mashour, Matthew J. O’Meara, Jonathan Z. Sexton
    bioRxiv 2020.05.27.117184; doi: https://doi.org/10.1101/2020.05.27.117184
    Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    Citation Tools
    Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19
    Carmen Mirabelli, Jesse W. Wotring, Charles J. Zhang, Sean M. McCarty, Reid Fursmidt, Tristan Frum, Namrata S. Kadambi, Anya T. Amin, Teresa R. O’Meara, Carla D. Pretto, Jason R. Spence, Jessie Huang, Konstantinos D. Alysandratos, Darrell N. Kotton, Samuel K. Handelman, Christiane E. Wobus, Kevin J. Weatherwax, George A. Mashour, Matthew J. O’Meara, Jonathan Z. Sexton
    bioRxiv 2020.05.27.117184; doi: https://doi.org/10.1101/2020.05.27.117184

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Subject Area

    • Cell Biology
    Subject Areas
    All Articles
    • Animal Behavior and Cognition (2635)
    • Biochemistry (5223)
    • Bioengineering (3650)
    • Bioinformatics (15727)
    • Biophysics (7218)
    • Cancer Biology (5597)
    • Cell Biology (8051)
    • Clinical Trials (138)
    • Developmental Biology (4739)
    • Ecology (7472)
    • Epidemiology (2059)
    • Evolutionary Biology (10531)
    • Genetics (7702)
    • Genomics (10090)
    • Immunology (5156)
    • Microbiology (13828)
    • Molecular Biology (5354)
    • Neuroscience (30605)
    • Paleontology (212)
    • Pathology (872)
    • Pharmacology and Toxicology (1520)
    • Physiology (2235)
    • Plant Biology (4987)
    • Scientific Communication and Education (1037)
    • Synthetic Biology (1380)
    • Systems Biology (4131)
    • Zoology (804)