Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A(2)()

Nikolaou, Aikaterini; Kokotou, Maroula G.; Vasilakaki, Sofia; Kokotos, George

Phospholipase A(2) (PLA(2)) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA(2) inhibitors developed to target each one of the four major types of human PLA(2) (cytosolic cPLA(2), calcium-independent iPLA(2,) secreted sPLA(2,) and lipoprotein-associated LpPLA(2)). We discuss recent applications of inhibitors to understand the role of each PLA(2) type and their therapeutic potential. Potent and selective PLA(2) inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA(2) inhibitors are excellent tools to unveil the role that each PLA(2) type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA(2) inhibitors as new agents to treat inflammatory diseases.