PT  - JOURNAL ARTICLE
AU  - Nils C. Gassen
AU  - Jan Papies
AU  - Thomas Bajaj
AU  - Frederik Dethloff
AU  - Jackson Emanuel
AU  - Katja Weckmann
AU  - Daniel E. Heinz
AU  - Nicolas Heinemann
AU  - Martina Lennarz
AU  - Anja Richter
AU  - Daniela Niemeyer
AU  - Victor M. Corman
AU  - Patrick Giavalisco
AU  - Christian Drosten
AU  - Marcel A. Müller
TI  - Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics
AID  - 10.1101/2020.04.15.997254
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.15.997254
4099  - http://biorxiv.org/content/early/2020/04/15/2020.04.15.997254.short
4100  - http://biorxiv.org/content/early/2020/04/15/2020.04.15.997254.full
AB  - 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 StatementThe authors have declared no competing interest.