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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 sh...

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Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2022-08, Vol.15 (8)
Main Authors: Theodoropoulou, Maria A, Koutoulogenis, Giorgos S, Zhang, Linlin, Akrani, Ifigeneia, Mikros, Emmanuel, Hilgenfeld, Rolf, Kokotos, George
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container_title Pharmaceuticals (Basel, Switzerland)
container_volume 15
creator Theodoropoulou, Maria A
Koutoulogenis, Giorgos S
Zhang, Linlin
Akrani, Ifigeneia
Mikros, Emmanuel
Hilgenfeld, Rolf
Kokotos, George
description 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.
doi_str_mv 10.3390/ph15080961
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subjects Antiviral agents
Ethylenediaminetetraacetic acid
Health aspects
Identification and classification
Phospholipases
Physiological aspects
Protease inhibitors
Severe acute respiratory syndrome
Testing
title Identification of a Dual Inhibitor of Secreted Phospholipase A[sub.2] and SARS-CoV-2 Main Protease
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