Snake venom phospholipase A2s exhibit strong virucidal activity against SARS-CoV-2 and inhibit the viral spike glycoprotein interaction with ACE2

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 requires new treatments both to alleviate the symptoms and to prevent the spread of this disease. Previous studies demonstrated good antiviral and virucidal activity of phospholipase A₂s (PLA₂s) from snake venoms against viruses from different families but there was no data for coronaviruses. Here we show that PLA₂s from snake venoms protect Vero E6 cells against SARS-CoV-2 cytopathic effects. PLA₂s showed low cytotoxicity to Vero E6 cells with some activity at micromolar concentrations, but strong antiviral activity at nanomolar concentrations. Dimeric PLA₂ from the viper Vipera nikolskii and its subunits manifested especially potent virucidal effects, which were related to their phospholipolytic activity, and inhibited cell-cell fusion mediated by the SARS-CoV-2 spike glycoprotein. Moreover, PLA₂s interfered with binding both of an antibody against ACE2 and of the receptor-binding domain of the glycoprotein S to 293T/ACE2 cells. This is the first demonstration of a detrimental effect of PLA₂s on β-coronaviruses. Thus, snake PLA₂s are promising for the development of antiviral drugs that target the viral envelope, and could also prove to be useful tools to study the interaction of viruses with host cells.

Keywords: Molecular modelling; Pseudotyped SARS-CoV-2 virus; Receptor binding domain; Replication cycle; Surface plasmon resonance; Time-of-drug-addition assay.