Phospholipase A2 (PLA2) enzymes are the upstream regulators of the eicosanoid pathway liberating free arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA). The liberation of AA by PLA2 enzymes sets off a cascade of molecular events that involves downstream regulators such as cyclooxygenase (COX) and lipoxygenase (LOX) leading to inflammation.1 Aspirin and many other Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting COX and LOX in this cascade that rely on PLA2 enzymes to provide them with AA. That means PLA2 enzymes could potentially also be targeted to diminish inflammation at an earlier point in the process. Using molecular dynamics (MD) simulations guided by hydrogen/deuterium exchange mass spectrometric experimental data, we have recently elucidated the catalytic cycle of two intracellular enzymes: the cytosolic (cPLA2) and calcium-independent (iPLA2). cPLA2 is the main AA provider of the eicosanoid pathway, while iPLA2 is mainly involved in membrane phospholipid remodeling. Our data showed the channels to the active sites of these PLA2s are opened upon allosteric interaction of the enzyme interfacial surface with the membrane to facilitate entry of the substrate phospholipid. This constitutes the first detailed study describing the binding and the interaction mechanism of two intracellular PLA2s with the membrane bilayer as well as how they bind a single phospholipid molecule in the catalytic site.2 Similar methods were also employed to understand the binding of various inhibitors to generate structure-activity relationships that facilitate the development of new potent and selective inhibitors for these two enzymes. In fact, we have developed thioether fluoroketone compounds that selectively inhibit iPLA2 versus cPLA2.3, 4 These enzymes are implicated in many chronic inflammatory diseases and the development of potent and selective inhibitors will aid in the discovery of new anti-inflammatory therapeutic agents.

Targeting phospholipase A<sub>2 </sub>to diminish inflammation by developing novel inhibitors

253rd National Meeting (2017)

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Targeting phospholipase A2 to diminish inflammation by developing novel inhibitors

Targeting phospholipase A₂to diminish inflammation by developing novel inhibitors