Alternative Targets for sPLA2 Activity: Role of Membrane-Enzyme Interactions

The secreted phospholipases A2 (sPLA2s) play important roles both physiologically and pathologically, with their expression increasing significantly in diseases such as sepsis, inflammation, different cancers, glaucoma, obesity, Alzheimer's disease and even COVID-19. The fact has led to a large-scale search for inhibitors of these enzymes. In total, several dozen promising molecules have been proposed, but not a single one has successfully passed clinical trials. The failures in clinical studies motivated in-depth fundamental studies of PLA2s. Here we review alternative ways to control sPLA2 activity, outside its catalytic site. The concept can be realized by preventing sPLA2 from attaching to the membrane surface; by binding to an external protein which blocks sPLA2 hydrolytic activity; by preventing sPLA2 from orienting properly on the membrane surface; and by preventing substrate binding to the enzyme, keeping the catalytic site unaltered. Evidence in the literature is summarized in the review with the aim to serve as a starting point for new types of sPLA2 inhibitors.