In Silico Study of Polyunsaturated Fatty Acids as Potential SARS-CoV-2 Spike Protein Closed Conformation Stabilizers: Epidemiological and Computational Approaches

Abstract

SARS-CoV-2 infects host cells by interacting its spike protein with surface angiotensin-converting enzyme 2 (ACE2) receptors, expressed in lung and other cell types. Although several risk factors could explain why some countries have lower incidence and fatality rates than others, environmental factors such as diet should be considered. It has been described that countries with high polyunsaturated fatty acid (PUFA) intake have a lower number of COVID-19 victims and a higher rate of recovery from the disease. Moreover, it was found that linoleic acid, an omega-6 PUFA, could stabilize the spike protein in a closed conformation, blocking its interaction with ACE2. These facts prompted us to perform in silico simulations to determine if other PUFA could also stabilize the closed conformation of spike protein and potentially lead to a reduction in SARS-CoV-2 infection. We found that: (a) countries whose source of omega-3 is from marine origin have lower fatality rates; and (b) like linoleic acid, omega-3 PUFA could also bind to the closed conformation of spike protein and therefore, could help reduce COVID-19 complications by reducing viral entrance to cells, in addition to their known anti-inflammatory effects.

Effect of immunonutrition on serum levels of C-reactive protein and lymphocytes in patients with COVID-19: a randomized, controlled, double-blind clinical trial

“…One of the hypotheses that could explain how ω-3 fatty acids can interfere with the inflammation caused by SARS-CoV-2 is that this substance could bind to the three-dimensional conformation of the spike protein(21) and modify it. This protein is used by the coronavirus to enter cells and infect them.…”

Predicting global diet-disease relationships at the atomic level: a COVID-19 case study

“…Reviewing the results from multiple studies can provide additional context for the findings from standalone studies. Fatty acids, for example, may still offer protective roles against COVID-19 despite low predicted association with SARS-CoV-2 M pro [ 22 • ] by complexing with other viral targets [ 57 • ]. Similarly, although organosulfur compounds such as diallyl disulfide and diallyl trisulfide from garlic ranked relatively low among spice compounds in docking scores for M pro [ 30 , 37 ], further investigation into these compounds may still be warranted due to their abundance in garlic oil – together accounting for over 51% of constituents – and predicted affinity for multiple viral targets [ 45 ].…”

“…The use of molecular docking in food and nutritional sciences to explain or theorize relationships between diet and disease susceptibility has emerged during the pandemic. When epidemiological analysis revealed that countries with marine-sourced dietary omega-3 fatty acids had lower fatality rates of COVID-19, Vivar-Sierra et al [ 57 • ] used molecular docking results to help propose that a possible explanation was impeded host entry due to omega-3 fatty acids reinforcing the closed (i.e., inaccessible) conformation of the SARS-CoV-2 spike protein. Chowdhury et al [ 58 ] used molecular docking to suggest that the strong association predicted between choline and SARS-CoV-2 M pro could help explain earlier observations that higher choline levels in expecting mothers who were infected with COVID-19 may have protective effects for fetal brain development.…”

Thiol-based mucolytics exhibit antiviral activity against SARS-CoV-2 through allosteric disulfide disruption in the spike glycoprotein

“…This pocket, shown in Figure 5a, associates with hydrophobic molecules, e.g., linoleic acid, even in the closed state of SARS-CoV-2 and related coronavirus spike proteins. [38][39][40] The binding of hydrophobic molecules to this pocket has been related to stabilization of spike protein in its closed conformation, 38,41 and ligands such as polyunsaturated fatty acids or lipid-soluble vitamins have shown to inhibit SARS-CoV-2 RBD-ACE2 binding in vitro. 42 When analyzing the dynamic behavior of the isolated RBD or its open conformation in the spike protein after extensive MD simulations, this pocket proved to be cryptic, characterized by breathing-like dynamics that allow transient accessibility to the Cys379-Cys432 disulfide (Figure 5 and Figure S4).…”