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

ACS Central Science, vol. 10, pp. 1594–1608

Abstract

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.

Authors 19

1. Melissa Thaler Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

2. Tim P. Ofman Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

3. Ken Kok Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

4. Jurriaan J. A. Heming Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

5. E. J. MORAN

   University of York

   Affiliation as printed

   Department of Chemistry, University of York, York YO10 5DD, United Kingdom

6. Isabelle B. Pickles

   University of York

   Affiliation as printed

   Department of Chemistry, University of York, York YO10 5DD, United Kingdom

7. Anouk A. Leijs Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

8. Adrianus M. C. H. van den Nieuwendijk Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

9. Richard J. B. H. N. van den Berg Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

10. Gijs Ruijgrok Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

11. Zachary Armstrong Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

12. Clarisse Salgado‐Benvindo Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

13. Dennis K. Ninaber Aachen Dept of Pulmonology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pulmonology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

14. Eric J. Snijder Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

15. Constant A. A. van Boeckel Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

16. Marta Artola Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

17. G.J. Davies

    University of York

    Affiliation as printed

    Department of Chemistry, University of York, York YO10 5DD, United Kingdom

18. Herman S. Overkleeft corresponding Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University, 2311 EZ Leiden, The Netherlands

19. Martijn J. van Hemert corresponding Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands