Epi -Cyclophellitol Cyclosulfate, a Mechanism-Based Endoplasmic Reticulum α-Glucosidase II Inhibitor, Blocks Replication of SARS-CoV-2 and Other Coronaviruses

作者：Melissa Thaler, Tim P. Ofman, Ken Kok, Jurriaan J. A. Heming, E. J. MORAN, Isabelle B. Pickles, Anouk A. Leijs, Adrianus M. C. H. van den Nieuwendijk, Richard J. B. H. N. van den Berg, Gijs Ruijgrok, Zachary Armstrong, Clarisse Salgado‐Benvindo, Dennis K. Ninaber, Eric J. Snijder, C. A. A. VAN BOECKEL, Marta Artola, G.J. Davies, Herman S. Overkleeft, Martijn J. van Hemert · 发表于：ACS Central Science · 年份：2024 · DOI：10.1021/acscentsci.4c00506 · 被引用次数：4 · 研究领域：SARS-CoV-2 and COVID-19 Research、Endoplasmic Reticulum Stress and Disease、Calcium signaling and nucleotide metabolism

High Resolution Image Download MS PowerPoint Slide The combined inhibition of endoplasmic reticulum (ER) α-glucosidases I and II has been shown to inhibit replication of a broad range of viruses that rely on ER protein quality control. We found, by screening a panel of deoxynojirimycin and cyclitol glycomimetics, that the mechanism-based ER α-glucosidase II inhibitor, 1,6- epi -cyclophellitol cyclosulfate, potently blocks SARS-CoV-2 replication in lung epithelial cells, halting intracellular generation of mature spike protein, reducing production of infectious progeny, and leading to reduced syncytium formation. Through activity-based protein profiling, we confirmed ER α-glucosidase II inhibition in primary airway epithelial cells, grown at the air–liquid interface. 1,6- epi -Cyclophellitol cyclosulfate inhibits early pandemic and more recent SARS-CoV-2 variants, as well as SARS-CoV and MERS-CoV. The reported antiviral activity is comparable to the best-in-class described glucosidase inhibitors, all competitive inhibitors also targeting ER α-glucosidase I and other glycoprocessing enzymes not involved in ER protein quality control. We propose selective blocking ER-resident α-glucosidase II in a covalent and irreversible manner as a new strategy in the search for effective antiviral agents targeting SARS-CoV-2 and other viruses that rely on ER protein quality control.