Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease
The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M<sup>pro</sup>) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/8/961 |
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| author | Maria A. Theodoropoulou Giorgos S. Koutoulogenis Linlin Zhang Ifigeneia Akrani Emmanuel Mikros Rolf Hilgenfeld George Kokotos |
| author_facet | Maria A. Theodoropoulou Giorgos S. Koutoulogenis Linlin Zhang Ifigeneia Akrani Emmanuel Mikros Rolf Hilgenfeld George Kokotos |
| author_sort | Maria A. Theodoropoulou |
| collection | DOAJ |
| description | The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M<sup>pro</sup>) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of COVID-19 has shown that lipids and lipid metabolizing enzymes are critically involved in the severity of the infection. The purpose of the present study was to identify an inhibitor able to simultaneously inhibit both SARS-CoV-2 M<sup>pro</sup> and phospholipase A<sub>2</sub> (PLA<sub>2</sub>), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA<sub>2</sub> inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA<sub>2</sub>, GK241, may also weakly inhibit SARS-CoV-2 M<sup>pro</sup>. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 M<sup>pro</sup>. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA<sub>2</sub> and SARS-CoV-2 M<sup>pro</sup> inhibitors. |
| first_indexed | 2024-03-09T09:51:14Z |
| format | Article |
| id | doaj.art-ba24c522754a4ad8a17961b5bf96bafd |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T09:51:14Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-ba24c522754a4ad8a17961b5bf96bafd2023-12-02T00:08:54ZengMDPI AGPharmaceuticals1424-82472022-08-0115896110.3390/ph15080961Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main ProteaseMaria A. Theodoropoulou0Giorgos S. Koutoulogenis1Linlin Zhang2Ifigeneia Akrani3Emmanuel Mikros4Rolf Hilgenfeld5George Kokotos6Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, GreeceDepartment of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, GreeceInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyDepartment of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, GreeceDepartment of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, GreeceInstitute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, GermanyDepartment of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, GreeceThe development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M<sup>pro</sup>) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of COVID-19 has shown that lipids and lipid metabolizing enzymes are critically involved in the severity of the infection. The purpose of the present study was to identify an inhibitor able to simultaneously inhibit both SARS-CoV-2 M<sup>pro</sup> and phospholipase A<sub>2</sub> (PLA<sub>2</sub>), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA<sub>2</sub> inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA<sub>2</sub>, GK241, may also weakly inhibit SARS-CoV-2 M<sup>pro</sup>. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 M<sup>pro</sup>. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA<sub>2</sub> and SARS-CoV-2 M<sup>pro</sup> inhibitors.https://www.mdpi.com/1424-8247/15/8/961COVID-19inhibitorsmain protease2-oxoamidesphospholipase A<sub>2</sub>SARS-CoV-2 |
| spellingShingle | Maria A. Theodoropoulou Giorgos S. Koutoulogenis Linlin Zhang Ifigeneia Akrani Emmanuel Mikros Rolf Hilgenfeld George Kokotos Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease Pharmaceuticals COVID-19 inhibitors main protease 2-oxoamides phospholipase A<sub>2</sub> SARS-CoV-2 |
| title | Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease |
| title_full | Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease |
| title_fullStr | Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease |
| title_full_unstemmed | Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease |
| title_short | Identification of a Dual Inhibitor of Secreted Phospholipase A<sub>2</sub> (GIIA sPLA<sub>2</sub>) and SARS-CoV-2 Main Protease |
| title_sort | identification of a dual inhibitor of secreted phospholipase a sub 2 sub giia spla sub 2 sub and sars cov 2 main protease |
| topic | COVID-19 inhibitors main protease 2-oxoamides phospholipase A<sub>2</sub> SARS-CoV-2 |
| url | https://www.mdpi.com/1424-8247/15/8/961 |
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