TY - JOUR
T1 - Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro
AU - Jan, Zainab
AU - Geethakumari, Anupriya M.
AU - Biswas, Kabir H.
AU - Jithesh, Puthen Veettil
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - 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 aim of this work was to identify an effective inhibitor of Mpro. 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.
AB - 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 aim of this work was to identify an effective inhibitor of Mpro. 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.
KW - BRET assay
KW - COVID-19
KW - M
KW - Protegrin-2
KW - SARS-CoV-2, antimicrobial peptides
UR - http://www.scopus.com/inward/record.url?scp=85165654443&partnerID=8YFLogxK
U2 - 10.1016/j.csbj.2023.07.020
DO - 10.1016/j.csbj.2023.07.020
M3 - Article
AN - SCOPUS:85165654443
SN - 2001-0370
VL - 21
SP - 3665
EP - 3671
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -