Secreted phospholipase A2 enzymes as therapeutic targets.

Homology cloning through in silico database search analysis has led to the definition of ten structurally-related mammalian secreted phospholipase A(2) (sPLA(2)) enzyme forms at present, each expressed in a species-, genotype- and cell-type-specific manner and with different enzymatic properties. These studies have shown that models based on the premise that there is only one PLA(2) drug target are now inadequate. Type IIA sPLA(2) remains the most advanced clinical target, with rationally designed inhibitors in Phase II clinical trials. However, progress in our understanding of the functional role of the ten secreted enzymes in phospholipid (PL) metabolism and in eicosanoid-mediated disorders, together with their emerging activity-independent and receptor-mediated functions, is likely to significantly impact on current and future drug development efforts.