Background
SARS-CoV-2 variants continue to spread throughout the world and cause waves of COVID-19 infections. It is important to find effective antiviral drugs to combat SARS-CoV-2 and its variants. The main protease (Mpro) of SARS-CoV-2 is a promising therapeutic target due to its crucial role in viral replication and its conservation in all the variants. Therefore, the
Conclusions
Our in silico and experimental studies identified Protegrin-2 as a potent inhibitor of Mpro that could be pursued further towards drug development against COVID-19 infection.
Methods
We studied around 200 antimicrobial peptides using in silico methods including molecular docking and allergenicity and toxicity prediction. One selected antiviral peptide was studied experimentally using a Bioluminescence Resonance Energy Transfer (BRET)-based Mpro biosensor, which reports Mpro activity through a decrease in energy transfer.
Results
Molecular docking identified one natural antimicrobial peptide, Protegrin-2, with high binding affinity and stable interactions with Mpro allosteric residues. Furthermore, free energy calculations and molecular dynamics simulation illustrated a high affinity interaction between the two. We also determined the impact of the binding of Protegrin-2 to Mpro using a BRET-based assay, showing that it inhibits the proteolytic cleavage activity of Mpro. Conclusions: Our in silico and experimental studies identified Protegrin-2 as a potent inhibitor of Mpro that could be pursued further towards drug development against COVID-19 infection.