Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry

Area of Science:

• Virology
• Biochemistry
• Drug Discovery

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, a global pandemic.
• Lipids are known for antiviral properties, but their specific effects on SARS-CoV-2 binding and entry are not well understood.

Purpose of the Study:

• To investigate the anti-SARS-CoV-2 potential of various lipid compounds, including fatty acids and fat-soluble vitamins.
• To identify specific lipids that can inhibit viral binding and entry mechanisms.

Main Methods:

• Screening of 17 different fatty acids (polyunsaturated, monounsaturated, saturated) and lipid-soluble vitamins.
• Target-based ligand screening using the SARS-CoV-2 Receptor Binding Domain (RBD) sequence.
• Pseudovirus assay using a spike protein to evaluate viral entry inhibition.
• Assessing the impact of fatty acids on TMPRSS2 and cathepsin L protease activity and expression.

Main Results:

• Polyunsaturated fatty acids demonstrated the most effective interference with SARS-CoV-2 binding to the human ACE2 (hACE2) receptor.
• Linolenic acid and eicosapentaenoic acid significantly inhibited SARS-CoV-2 entry.
• Eicosapentaenoic acid was more effective than linolenic acid in reducing TMPRSS2 and cathepsin L protease activity without altering their protein expression.
• No reduction in hACE2 activity or binding was observed with these fatty acids.

Conclusions:

• This study identifies specific fatty acids, notably linolenic and eicosapentaenoic acid, as inhibitors of SARS-CoV-2 binding and entry.
• Lipids, particularly polyunsaturated fatty acids, represent a promising class of compounds for developing novel antiviral strategies against SARS-CoV-2.
• Further in vivo studies are necessary to confirm these findings and explore therapeutic applications.