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) metabolites leading to inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting COX and LOX which both rely on PLA2 enzymes to provide them with AA. That means PLA2 enzymes can potentially also be targeted to diminish inflammation at an earlier point in the process. Structure-activity relationship correlations were generated using a set of fluoroketones that are potent inhibitors for calcium-independent PLA2. Virtual screening techniques were used to select a set of compounds from commercially available databases of small organic molecules. These compounds were ordered and screened in vitro for inhibitory activity against calcium-independent PLA2. The active compounds were also tested against cytosolic and secreted PLA2 for selectivity. This study let to the identification of hit compounds that were evaluated in a cell-based assay. Lipidomics analysis showed that the hit compounds penetrate macrophages and reduce the production of inflammatory mediators by inhibiting PLA2. These compounds will undergo lead optimization to improve inhibitory potency against calcium-independent PLA2. This enzyme is implicated in rare inflammatory and genetic diseases, and the development of potent and selective inhibitors will aid in the discovery of new therapeutics.

Phospholipase A2: A target for the development of anti-inflammatory agents

255th National Meeting (2018)

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