Phospholipases A2 (PLA2s) are enzymes that cleave fatty acid in position two of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule. PLA2s are key enzymes involved in many events in cellular signaling. Moreover, PLA2 enzymes are commonly found in mammalian tissues as well as arachnid, insect, and snake venom. Among them, snake venom PLA2s can cause pre-synaptic and/or post-synaptic neurotoxicity, myotoxicity, and cardiotoxicity, which can induce platelet aggregation disorders, hemolysis, anticoagulation, and necrosis.
Varespladib (also known as LY315920) is a potent, selective and orally active group IIA, secretory phospholipase A2 (sPLA2) inhibitor. However, Varespladib shows 40-fold less active against human, group IB, pancreatic sPLA2. In addition, it exhibits inactive against cytosolic PLA2 and the constitutive and inducible forms of cyclooxygenase. Varespladib exhibits the significant inhibitory effect on sPLA2 activity in serum from various species including rat, rabbit, and guinea pig. For example, intravenous or oral administration of Varespladib to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-dependent manner. Varespladib inhibits human sPLA2-induced release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells. Furthermore, Varespladib is not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities induced by venom toxins.
In summary, Varespladib is a selective and orally active group IIA, sPLA2 inhibitor, has anti-inflammatory effects, and mitigates the toxic effects of certain snakebites.