Identification of a Dual Inhibitor of Secreted Phospholipase A[sub.2] 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] ) 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] and phospholipase A[sub.2] (PLA[sub.2] ), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA[sub.2] inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA[sub.2] , GK241, may also weakly inhibit SARS-CoV-2 M[sup.pro] . Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 M[sup.pro] . 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA[sub.2] and SARS-CoV-2 M[sup.pro] inhibitors.