Identification of a Dual Inhibitor of Secreted Phospholipase A2 (GIIA sPLA2) and SARS-CoV-2 Main Protease

Maria A Theodoropoulou; Giorgos S Koutoulogenis; Linlin Zhang; Ifigeneia Akrani; Emmanuel Mikros; Rolf Hilgenfeld; George Kokotos

doi:10.3390/ph15080961

Identification of a Dual Inhibitor of Secreted Phospholipase A₂ (GIIA sPLA₂) and SARS-CoV-2 Main Protease

Pharmaceuticals (Basel). 2022 Aug 3;15(8):961. doi: 10.3390/ph15080961.

Authors

Maria A Theodoropoulou^{1

2}, Giorgos S Koutoulogenis^{1

2}, Linlin Zhang³, Ifigeneia Akrani⁴, Emmanuel Mikros^{4

5}, Rolf Hilgenfeld^{3

6}, George Kokotos^{1

2}

Affiliations

¹ Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece.
² Center of Excellence for Drug Design and Discovery, National and Kapodistrian University of Athens, 15771 Athens, Greece.
³ Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
⁴ Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece.
⁵ Athena Research and Innovation Center in Information Communication & Knowledge Technologies, 15125 Marousi, Greece.
⁶ German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.

Abstract

The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M^pro) 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^pro and phospholipase A₂ (PLA₂), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA₂ inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA₂, GK241, may also weakly inhibit SARS-CoV-2 M^pro. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 M^pro. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA₂ and SARS-CoV-2 M^pro inhibitors.

Keywords: 2-oxoamides; COVID-19; SARS-CoV-2; inhibitors; main protease; phospholipase A2.

Abstract

Grants and funding