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Pharmaceuticals (Basel) ; 15(8)2022 Aug 03.
Article in English | MEDLINE | ID: covidwho-1969411


The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (Mpro) 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 Mpro 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 Mpro. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 Mpro. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA2 and SARS-CoV-2 Mpro inhibitors.

Expert Opin Drug Discov ; 17(3): 231-246, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1649006


INTRODUCTION: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the devastating pandemic named coronavirus disease 2019 (COVID-19). Unfortunately, the discovery of antiviral agents to combat COVID-19 is still an unmet need. Transmembrane serine protease 2 (TMPRSS2) is an important mediator in viral infection and thus, TMPRRS2 inhibitors may be attractive agents for COVID-19 treatment. AREAS COVERED: This review article discusses the role of TMPRSS2 in SARS-CoV-2 cell entry and summarizes the inhibitors of TMPRSS2 and their potential anti-SARS activity. Two known TMPRSS2 inhibitors, namely camostat and nafamostat, approved drugs for the treatment of pancreatitis, are under clinical trials as potential drugs against COVID-19. EXPERT OPINION: Due to the lack of the crystal structure of TMPRSS2, homology models have been developed to study the interactions of known inhibitors, including repurposed drugs, with the enzyme. However, novel TMPRSS2 inhibitors have been identified through high-throughput screening, and appropriate assays studying their in vitro activity have been set up. The discovery of TMPRSS2's crystal structure will facilitate the rational design of novel inhibitors and in vivo studies and clinical trials will give a clear answer if TMPRSS2 inhibitors could be a new weapon against COVID-19.

COVID-19 , Serine Endopeptidases , Virus Internalization , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Protease Inhibitors/pharmacology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
Expert Opin Drug Discov ; 16(11): 1287-1305, 2021 11.
Article in English | MEDLINE | ID: covidwho-1276091


AREAS COVERED: This review article summarizes the most important synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated Lp-PLA2), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA2 in the pathobiology of COVID-19 are also discussed. EXPERT OPINION: Although a number of PLA2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA2, varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal.

COVID-19/drug therapy , Drug Design , Drug Discovery , Inflammation/drug therapy , Phospholipase A2 Inhibitors/therapeutic use , Humans , SARS-CoV-2