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

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

Nils C. Gassen, Jan Papies, Thomas Bajaj, Frederik Dethloff, Jackson Emanuel, Katja Weckmann, Daniel E. Heinz, Nicolas Heinemann, Martina Lennarz, Anja Richter, Daniela Niemeyer, Victor M. Corman, Patrick Giavalisco, Christian Drosten, Marcel A. Müller
doi: https://doi.org/10.1101/2020.04.15.997254
Nils C. Gassen
1Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: nils.gassen@ukbonn.de marcel.mueller@charite.de
Jan Papies
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Bajaj
1Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frederik Dethloff
4Max Planck Institute for Aging, 50931 Cologne, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jackson Emanuel
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katja Weckmann
1Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel E. Heinz
1Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicolas Heinemann
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martina Lennarz
1Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anja Richter
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniela Niemeyer
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Victor M. Corman
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick Giavalisco
4Max Planck Institute for Aging, 50931 Cologne, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Drosten
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marcel A. Müller
2Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3German Centre for Infection Research (DZIF), partner site Charité, 10117 Berlin, Germany
5Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, 119991 Moscow, Russia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: nils.gassen@ukbonn.de marcel.mueller@charite.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an acute threat to public health and the world economy, especially because no approved specific drugs or vaccines are available. Pharmacological modulation of metabolism-dependent cellular pathways such as autophagy reduced propagation of highly pathogenic Middle East respiratory syndrome (MERS)-CoV.

Here we show that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic pathways and that compound-driven interventions aimed at autophagy induction reduce SARS-CoV-2 propagation in vitro. In-depth analyses of autophagy signaling and metabolomics indicate that SARS-CoV-2 reduces glycolysis and protein translation by limiting activation of AMP-protein activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Infection also downregulates autophagy-inducing spermidine, and facilitates AKT1/SKP2-dependent degradation of autophagy-initiating Beclin-1 (BECN1). Targeting of these pathways by exogenous administration of spermidine, AKT inhibitor MK-2206, and the Beclin-1 stabilizing, antihelminthic drug niclosamide inhibited SARS-CoV-2 propagation by 85, 88, and >99%, respectively. In sum, SARS-CoV-2 infection causally diminishes autophagy. A clinically approved and well-tolerated autophagy-inducing compound shows potential for evaluation as a treatment against SARS-CoV-2.

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. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted April 15, 2020.
Download PDF

Supplementary Material

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.
Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics
(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
Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics
Nils C. Gassen, Jan Papies, Thomas Bajaj, Frederik Dethloff, Jackson Emanuel, Katja Weckmann, Daniel E. Heinz, Nicolas Heinemann, Martina Lennarz, Anja Richter, Daniela Niemeyer, Victor M. Corman, Patrick Giavalisco, Christian Drosten, Marcel A. Müller
bioRxiv 2020.04.15.997254; doi: https://doi.org/10.1101/2020.04.15.997254
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics
Nils C. Gassen, Jan Papies, Thomas Bajaj, Frederik Dethloff, Jackson Emanuel, Katja Weckmann, Daniel E. Heinz, Nicolas Heinemann, Martina Lennarz, Anja Richter, Daniela Niemeyer, Victor M. Corman, Patrick Giavalisco, Christian Drosten, Marcel A. Müller
bioRxiv 2020.04.15.997254; doi: https://doi.org/10.1101/2020.04.15.997254

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

  • Microbiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4399)
  • Biochemistry (9637)
  • Bioengineering (7128)
  • Bioinformatics (24959)
  • Biophysics (12679)
  • Cancer Biology (10003)
  • Cell Biology (14406)
  • Clinical Trials (138)
  • Developmental Biology (7992)
  • Ecology (12155)
  • Epidemiology (2067)
  • Evolutionary Biology (16031)
  • Genetics (10957)
  • Genomics (14785)
  • Immunology (9911)
  • Microbiology (23750)
  • Molecular Biology (9517)
  • Neuroscience (51103)
  • Paleontology (370)
  • Pathology (1547)
  • Pharmacology and Toxicology (2694)
  • Physiology (4038)
  • Plant Biology (8700)
  • Scientific Communication and Education (1512)
  • Synthetic Biology (2406)
  • Systems Biology (6461)
  • Zoology (1350)