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

Gorshkov, Kirill; Chen, Catherine Z.; Bostwick, Robert; Rasmussen, Lynn; Xu, Miao; Pradhan, Manisha; Tran, Bruce Nguyen; Zhu, Wei; Shamim, Khalida; Huang, Wenwei; Hu, Xin; Shen, Min; Klumpp-Thomas, Carleen; Itkin, Zina; Shinn, Paul; Simeonov, Anton; Michael, Sam; Hall, Matthew D.; Lo, Donald C.; Zheng, Wei

SARS-CoV-02 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 EC(50) 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.