PHOSPHOLIPASE A2 IN AIRWAY DISEASES: TARGET FOR DRUG DISCOVERY

Abstract

Importance of the Field:

Inflammatory airway diseases are on the rise world over. There is need for orally active, safe and efficacious anti-inflammatory 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 rate-limiting 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.

Key Words: PLA2, Airway Inflammation, Asthma