The SARS-CoV-2 Cytopathic Effect Is Blocked by Lysosome Alkalizing Small Molecules
Kirill Gorshkov, Catherine Z. Chen, Robert Bostwick, Lynn Rasmussen, Bruce Nguyen Tran, Yu-Shan Cheng, Miao Xu, Manisha Pradhan, Mark J. Henderson, Wei Zhu, Eunkeu Oh, Kimihiro Susumu, Mason A. Wolak, Khalida Shamim, Wenwei Huang, Xin Hu, Min Shen, Carleen Klumpp‐Thomas, Zina Itkin, Paul Shinn, Juan Carlos de la Torre, Anton Simeonov, Sam Michael, Matthew D. Hall, Donald C. Lo, Wei Zheng
Abstract
) ranging from 1.5- to >10-fold. The compounds (1) blocked lysosome functioning and autophagy, (2) prevented pseudotyped particle entry, (3) increased lysosomal pH, and (4) reduced (ROC-325) viral titers in the EpiAirway 3D tissue model. Consistent with these findings, the siRNA knockdown of ATP6V0D1 blocked the HCoV-NL63 cytopathic effect in LLC-MK2 cells. Moreover, an analysis of SARS-CoV-2 infected Vero E6 cell lysate revealed significant dysregulation of autophagy and lysosomal function, suggesting a contribution of the lysosome to the life cycle of SARS-CoV-2. Our findings suggest the lysosome as a potential host cell target to combat SARS-CoV-2 infections and inhibitors of lysosomal function could become an important component of drug combination therapies aimed at improving treatment and outcomes for COVID-19.