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

Abstract

The strain SARS-CoV-2, newly emerged in late 2019, has been identified as the cause of COVID-19 and the pandemic declared by WHO in early 2020. Although lipids have been shown to possess antiviral efficacy, little is currently known about lipid compounds with anti-SARS-CoV-2 binding and entry properties. To address this issue, we screened, overall, 17 polyunsaturated fatty acids, monounsaturated fatty acids and saturated fatty acids, as wells as lipid-soluble vitamins. In performing target-based ligand screening utilizing the RBD-SARS-CoV-2 sequence, we observed that polyunsaturated fatty acids most effectively interfere with binding to hACE2, the receptor for SARS-CoV-2. Using a spike protein pseudo-virus, we also found that linolenic acid and eicosapentaenoic acid significantly block the entry of SARS-CoV-2. In addition, eicosapentaenoic acid showed higher efficacy than linolenic acid in reducing activity of TMPRSS2 and cathepsin L proteases, but neither of the fatty acids affected their expression at the protein level. Also, neither reduction of hACE2 activity nor binding to the hACE2 receptor upon treatment with these two fatty acids was observed. Although further in vivo experiments are warranted to validate the current findings, our study provides a new insight into the role of lipids as antiviral compounds against the SARS-CoV-2 strain.

Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions

“…SARS-CoV-2 spike-protein-expressing cells binding to soluble hACE2. To transduce cells with eGFP-luciferase-SARS-CoV-2 spike S1 lentivirus vector (GenScript, Piscataway, NJ), A549 cells, seeded into a 6-well plate in the presence of complete growth medium, were treated with 8 μl/ml polybrene (Sigma, St. Louis, MO) for 30 min., followed by the addition of eGFPluciferase-SARS-CoV-2 spike S1 lentivirus at MOI = 40 [51], and spin-inoculation at 1,000 x g. for 1.5h. After 24h at 37˚C incubation, cells were fed with fresh complete growth medium.…”

The roles of lipids in SARS-CoV-2 viral replication and the host immune response

“…A similar fatty acid binding pocket was also observed in SARS-CoV and MERS-CoV ( 40 ). It has also been reported that omega-3 fatty acids, including linoleic acid and eicosapentaenoic acid (EPA), can interact with the receptor binding domain of the SARS-CoV-2 S protein and inhibit attachment to the ACE2 receptor in vitro ( 41 ).…”

The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19

“…To date, sparse evidence has implicated omega-3 fatty acids in the prevention and treatment of COVID-19 [ 106 , 107 ]. Nevertheless, it has been shown that the omega-3 PUFAs inactivate enveloped viruses like SARS-CoV2 and inhibit ACE2-mediated binding and cellular entry of SARS-CoV-2 [ 108 ]. Furthermore, beneficial reports of omega-3 PUFAs have been reported in patients with sepsis and sepsis-induced ARDS [ 109 , 110 ].…”