A ricin-based peptide BRIP from Hordeum vulgare inhibits Mpro of SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 led to the research aiming to find the inhibitors of this virus. Towards this world problem, an attempt was made to identify SARS-CoV-2 main protease (M-pro) inhibitory peptides from ricin domains. The ricin-based peptide from barley (BRIP) was able to inhibit M-pro in vitro with an IC50 of 0.52 nM. Its low and no cytotoxicity upto 50 mu M suggested its therapeutic potential against SARS-CoV-2. The most favorable binding site on M-pro was identified by molecular docking and steered molecular dynamics (MD) simulations. The M-pro-BRIP interactions were further investigated by evaluating the trajectories for microsecond timescale MD simulations. The structural parameters of M-pro-BRIP complex were stable, and the presence of oppositely charged surfaces on the binding interface of BRIP and M-pro complex further contributed to the overall stability of the protein-peptide complex. Among the components of thermodynamic binding free energy, Van der Waals and electrostatic contributions were most favorable for complex formation. Our findings provide novel insight into the area of inhibitor development against COVID-19.

Automated summary

This study aimed to identify peptides that can inhibit the main protease (M-pro) of SARS-CoV-2, and a ricin-based peptide from barley (BRIP) was found to effectively inhibit M-pro and show potential therapeutic effects against SARS-CoV-2. Molecular docking and MD simulations revealed the favorable binding site and stable interactions between M-pro and BRIP. The findings provide new insights into inhibitor development against COVID-19.