Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S200103702300257X |
| _version_ | 1797384043211259904 |
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| author | Zainab Jan Anupriya M. Geethakumari Kabir H. Biswas Puthen Veettil Jithesh |
| author_facet | Zainab Jan Anupriya M. Geethakumari Kabir H. Biswas Puthen Veettil Jithesh |
| author_sort | Zainab Jan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T21:29:46Z |
| format | Article |
| id | doaj.art-0063b44eb4a949979fb0f5968a1c87a2 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T21:29:46Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-0063b44eb4a949979fb0f5968a1c87a22023-12-21T07:31:50ZengElsevierComputational and Structural Biotechnology Journal2001-03702023-01-012136653671Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease MproZainab Jan0Anupriya M. Geethakumari1Kabir H. Biswas2Puthen Veettil Jithesh3Division of Genomics and Translational Biomedicine, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, QatarDivision of Biological and Biomedical Sciences, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, QatarDivision of Biological and Biomedical Sciences, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar; Corresponding authors.Division of Genomics and Translational Biomedicine, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S200103702300257XMproCOVID-19SARS-CoV-2, antimicrobial peptidesBRET assayProtegrin-2 |
| spellingShingle | Zainab Jan Anupriya M. Geethakumari Kabir H. Biswas Puthen Veettil Jithesh Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro Computational and Structural Biotechnology Journal Mpro COVID-19 SARS-CoV-2, antimicrobial peptides BRET assay Protegrin-2 |
| title | Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro |
| title_full | Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro |
| title_fullStr | Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro |
| title_full_unstemmed | Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro |
| title_short | Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease Mpro |
| title_sort | protegrin 2 a potential inhibitor for targeting sars cov 2 main protease mpro |
| topic | Mpro COVID-19 SARS-CoV-2, antimicrobial peptides BRET assay Protegrin-2 |
| url | http://www.sciencedirect.com/science/article/pii/S200103702300257X |
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