Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease M <sup>pro</sup>
Zainab Jan, Anupriya M. Geethakumari, Kabir H. Biswas, Puthen V. Jithesh
Abstract
Abstract 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 (M pro ) 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 aim of this work was to identify an effective inhibitor of M pro . 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 M pro biosensor, which reports M pro 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 M pro 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 M pro using a BRET-based assay, showing that it inhibits the proteolytic cleavage activity of M pro . Conclusions Our in silico and experimental studies identified Protegrin-2 as a potent inhibitor of M pro that could be pursued further towards drug development against COVID-19 infection.