PHOSPHOLIPASE A2 IN AIRWAY DISEASES: TARGET FOR DRUG DISCOVERY
Journal Title: Journal of Drug Discovery and Therapeutics - Year 2013, Vol 1, Issue 8
Abstract
Importance of the Field: Inflammatory airway diseases are on the rise world over. There is need for orally active, safe and efficacious antiinflammatory agent. Existing therapeutic options are plagued by poor efficacy and adverse effects upon long term use. In our search for a novel drug discovery target, we tried to understand phospholipase A2 (PLA2) class of enzymes. Phospholipase A2, a major component of cell membranes, belongs to a family of enzymes that generate arachidonic acid and lysophospholipids from glycerophospholipids. PLA2 reaction is considered as the first ratelimiting step for the production of several lipid mediators notably arachidonic acid. Arachidonic acid, in turn, is metabolised to prostaglandins and leukotrienes. Importance of arachidonic acid metabolities in inflammation is well established. Inhibitors of prostaglandin and leukotriene biosynthesis have been approved as drugs for arthritis and asthma. Despite intensive research no PLA2 inhibitor has progressed through advanced clinical trials to become a drug. Area covered in this review: In this review, we shall look into different PLA2 enzymes and their role in generation of bioactive mediators. Drug discovery effort towards designing PLA2 inhibitors and the biological data generated thereof. No effort will be made to elaborate in detail biochemistry of PLA2 isoforms. We shall try to understand why in spite of controlling generation of all eicosanoids, PLA2 inhibitors did not show efficacy in clinical trials with special reference to respiratory diseases. What the reader will gain: An understanding of PLA2 enzymes and their role in generation of bioactive lipid mediators. Interference with PLA2 activity and its consequence on airway inflammation in experimental animals and in clinical trial will help us for better therapeutics with respect to inflammatory disorcders. Take home message: PLA2s are important enzymes of lipid membrane metabolism and plays a major role in etiology and pathology of inflammatory diseases. However, no drug has been approved from this target class as anti-inflammatory therapeutics, thus revisiting each enzyme, and target them selectively may prove a potential to the airway disorders.
Authors and Affiliations
Abhijit Ray| Department of Biology, Daiichi Sankyo India Pharma Pvt Ltd, Punit Kumar Srivastava*| Department of Biology, Daiichi Sankyo India Pharma Pvt Ltd
Keywords
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