Inhibition of Protein N-Glycosylation Blocks SARS-CoV-2 Infection

Area of Science:

• Virology
• Glycobiology
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes N-glycosylated spike proteins for host cell entry.
• These N-glycans are hypothesized to influence spike protein function, receptor binding, and immune evasion.

Purpose of the Study:

• To investigate the critical role of host N-glycosylation pathways and viral N-glycans in SARS-CoV-2 infection.
• To evaluate the potential of targeting N-glycosylation as a therapeutic strategy against SARS-CoV-2 and its variants.

Main Methods:

• Inhibition of host N-glycosylation using RNA interference and FDA-approved drugs.
• Enzymatic deglycosylation of intact SARS-CoV-2 virions.
• Assessment of viral spread, virion production, and infectivity in vitro.
• Testing against multiple SARS-CoV-2 variants including Alpha, Beta, Gamma, and Delta.

Main Results:

• Ablation of host N-glycosylation significantly reduced SARS-CoV-2 spread and infectivity across multiple variants.
• Cells with inhibited N-glycosylation produced fewer infectious virions.
• Surface-exposed N-glycans on virions were found to be essential for cell invasion.
• FDA-approved drugs targeting N-glycosylation demonstrated efficacy in reducing viral spread.

Conclusions:

• Protein N-glycosylation is a critical host-pathway and viral feature essential for SARS-CoV-2 infection.
• Targeting the N-glycosylation pathway presents a promising and potentially clinically relevant strategy for COVID-19 treatment.
• Repurposing existing drugs to inhibit viral glycosylation offers a complementary approach to vaccines for controlling COVID-19 spread, especially against emerging variants.