Editorial [Hot Topic: Phospholipase Inhibition: Medicinal Chemistry and Therapeutic Potential of PLA2 Inhibitors (Guest Editor: Dr. K.S. Rangappa)]

Phospholipase A2 (PLA2) enzymes are widely distributed in mammalian systems and in the venoms of snakes, bees, scorpions and spiders. Several isoforms of PLA2 enzymes are reported in mammalian system and the secretory isoform (sPLA2) exhibit strong homology with the snake venom PLA2s, which are again secretory in nature. sPLA2 enzymes from snake venom in spite of their strong homology are involved in wide variety of pharmacological activities. Role of sPLA2 enzyme in the manifestation of many inflammatory reactions in mammals is very well established. Apart from inflammatory reactions venom sPLA2 enzymes exhibit highly deleterious toxicities such as neurotoxicity (pre/post synaptic), cardiotoxicity, cytotoxicity, myotoxicity, nephrotoxicity, local tissue necrosis and also affect hemostasis (anti/pro coagulant). In some snake venoms these toxic PLA2s are the principal toxins in their venom composition. Since the catalytic sites are highly conserved in these sPLA2 enzymes inhibitors of venom sPLA2 enzymes also inhibit mammalian sPLA2 isoforms and vice versa. Due to these reasons, inhibitors of sPLA2 enzymes are immensely important as therapeutic agents against inflammation and venom toxicities. During inflammatory reactions, release of arachidonic acid in the free form is very critical for the synthesis of proinflammatory lipid mediators such as prostaglandins, leukotrienes and lipoxins. The other lipid mediator is platelet activating factor. Glucocortico steroids and their derivatives exert their powerful anti-inflammatory property by decreasing the levels of free arachidonic acid and their subsequent pro-inflammatory lipid mediators. How steroids decrease the level of free arachidonic acid is still not clear? The key enzyme involved in the release of arachidonic acid is PLA2 enzyme and for the subsequent synthesis of pro-inflammatory lipid mediators are cyclooxygenase and lipoxygenase enzymes. Clinical studies revealed that PLA2 enzyme action is the rate limiting step and in mammals sPLA2 isoforms are implicated as pro-inflammatory. Specific inhibitors of this isoforms could be used as anti-inflammatory drugs, which are as powerful as steroids. Knowing the importance of PLA2 inhibitors for their therapeutic applications many Pharmaceutical Industries and academic Institutions are involved in the search for novel specific PLA2 inhibitors. In literature, wide varieties of PLA2 inhibitors are reported. These inhibitors are characterized from plant sources, marine sponges, and animal sera. Based on these natural inhibitors, several new molecules were synthesized chemically and tested for PLA2 inhibition. By understanding the substrate nature and the active site of the molecules many substrates analogues were synthesized and tried for effective PLA2 inhibition. For snake venom sPLA2 enzymes, both polyclonal and monoclonal antibodies were raised. In spite of such a large variety of molecules only few molecules are there in the clinical trial and many of them are best suited for topical application only. In this special issue, review articles are invited from experts in the field of PLA2 enzymes searching for specific inhibitors. These reviews comprehensively cover the vast array of PLA2 inhibitory molecules and summarize the actual state and scope in the field of inflammation and venom toxicity. Two of the review articles from the laboratory of Prof. T. P. Singh et al., and Dr. K. Sekar discusses the binding characteristics of various PLA2 inhibitors (both natural and synthesized) at the molecular level in the co-crystallized enzyme-inhibitor complex. Prof. A.M. Soares and his group review the venom PLA2 inhibitors from wide range of sources that includes plant extracts and compounds from marine animals, mammals and snakes serum/plasma.....