New weapons against inflammation: dual inhibitors of phospholipase A2 and transglutaminase

Despite decades of research, corticosteroids and NSAIDs remain the main pharmacological weapons to control inflammation in the clinic.Unfortunately, these drugs have significant side effects, especially when used chronically.Consequently, there is tremendous interest in the development of novel, safer, and more effective anti-inflammatory drugs.Most antiinflammatory agents directly or indirectly inhibit the formation or the effects of arachidonic acid metabolites collectively known as eicosanoids (prostaglandins, leukotrienes, thromboxanes, endoperoxides, and other mediators) (Table 1).It has long been recognized that inhibition of phospholipase A 2 -catalyzed (PLA 2 -catalyzed) arachidonic acid release from cell-membrane glycerophospholipids could potentially block the synthesis of all eicosanoids.The vast PLA 2 enzyme family includes cellular isoforms involved in signal transduction, such as three cellular isoforms of PLA 2 (cPLA 2 s), and ten secretory isoforms of PLA 2 (sPLA 2 s) (1).Various sPLA 2 isoforms participate in digestive physiology, antimicrobial defense, and inflammation.