Potential of antiviral peptide-based SARS-CoV-2 inactivators to combat COVID-19

Abstract

The appearance of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lack of effective antiviral therapeutics for coronavirus disease 2019 (COVID-19), a highly infectious disease caused by the virus, demands the search for alternative therapies. Most antiviral drugs known are passive defenders which must enter the cell to execute their function and suffer from concerns such as permeability and effectiveness, therefore in this current study, we aim to identify peptide inactivators that can act without entering the cells. SARS-CoV-2 spike protein is an essential protein that plays a major role in binding to the host receptor angiotensin-converting enzyme 2 and mediates the viral cell membrane fusion process. SARS vaccines and treatments have also been developed with the spike protein as a target. The virtual screening experiment revealed antiviral peptides which were found to be non-allergen, non-toxic and possess good water solubility. U-1, GST-removed-HR2 and HR2-18 exhibit binding energies of -47.8 kcal/mol, -43.01 kcal/mol, and -40.46 kcal/mol, respectively. The complexes between these peptides and spike protein were stabilized through hydrogen bonds as well as hydrophobic interactions. The stability of the top-ranked peptide with the drug-receptor is evidenced by 50-ns molecular dynamics (MD) simulations. The binding of U-1 induces conformational changes in the spike protein with alterations in its geometric properties such as increased flexibility, decreased compactness, the increased surface area exposed to solvent molecules, and an increase in the number of total hydrogen bonds leading to its probable inactivation. Thus, the identified antiviral peptides can be used as anti-SARS-CoV-2 candidates, inactivating the virus's spike proteins and preventing it from infecting host cells.

Fig 1. Binding poses and molecular interactions of the top-ranked peptides with spike protein (A) U-1 (B) GST-removed-HR2 (C) HR2-18.

The green dashed line indicates the hydrogen bonds with distances labelled. The red and pink semi-arcs correspond to hydrophobic interacting residues of spike protein and peptide molecules respectively.

Fig 2. Plot of RMSD vs time (ps) for unbound spike protein (blue) and spike_U-1 complex (red).

Fig 3. Plot of RMSF vs residue for unbound spike protein (blue) and spike_U-1 complex (red).

Fig 4. Plot of Rg vs time (ps) for unbound spike protein (blue) and spike_U-1 complex (red).

Fig 5. Plot of number of Total SASA vs time (ps) for unbound spike protein (blue) and spike_U-1 complex (red).

Fig 6. Plot of number of hydrogen bonds vs time (ps) for unbound spike protein (blue) and spike_U-1 complex (red).