ABSTRACT
The recent COVID-19 pandemic shows the critical need for novel broad spectrum antiviral agents. Scorpion venoms are known to contain highly constrained peptides, several of which have demonstrated strong antiviral activity against a range of viruses. We have generated the first annotated reference transcriptome for the Androctonus amoreuxi venom gland and used transcriptome mining, circular dichroism and mass spectrometric analysis to characterize fifteen new venom peptides. Some of these peptides were tested for their ability to bind to the SARS-CoV-2 spike protein and to inhibit the spike RBD - hACE2 interaction that precedes virus entry into the cell using a surface plasmon resonance-based assay. Seven peptides showed dose-dependent inhibitory effects. The most active peptide was synthesized using solid phase peptide synthesis and tested for its antiviral activity against SARS-CoV-2 (Lineage B.1.1.7). On exposure of replication-competent SARS-CoV-2 to the synthetic peptide, we observed a two log10 PFU/mL reduction at sub-micromolar concentrations of the peptide compared to virus exposed to medium alone. Our results show that scorpion venom peptides could inhibit the SARS-CoV-2 spike RBD - hACE2 interaction, exhibit anti-SARS-CoV-2 activity through other unexplored modes of actions and represent excellent scaffolds for design of novel anti-SARS-CoV-2 constrained peptides.