Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.
Keywords: SARS-CoV-2; UV-4; castanospermine; celgosivir; iminosugar; virus.
【저자키워드】 SARS-CoV-2, virus., UV-4, castanospermine, celgosivir, iminosugar, 【초록키워드】 Treatment, viral infection, coronavirus, pandemic, glycosylation, spike, repurposing, Viral proteins, drug, virus, inhibitors, viral entry, Endoplasmic reticulum, Protein, Health, Culture, viral replication, Cell culture, death, VERO E6 cells, cell death, inhibitor, mechanism of action, Care, Interaction, acute respiratory syndrome, Viral protein, enzyme, dose-dependent manner, protein level, SARS-CoV-2 viral replication, active form, effective, shown, investigated, inhibit, required, reduced, prevented, reduction in, inhibiting, glycosylated, canonical, deoxynojirimycin, inhibit SARS-CoV-2, monocyclic, 【제목키워드】 Replication, inhibit SARS-CoV-2,