Phospholipase A2 (PLA2s) is an enzyme that cleaves fatty acids in the second position of phospholipids. Specifically, PLA2s can specifically recognize the sn-2 acyl bond of phospholipids and catalyze the hydrolysis of the bond. Thus, it releases arachidonic acid and lysophosphatidic acid.
Secreted phospholipases A2 (sPLA2) can catalyze the first step of the arachidonic acid pathway by decomposing phospholipids, thus promoting the inflammatory response in mammals. Besides, this leads to the formation of fatty acids including arachidonic acid. Moreover, the arachidonic acid is then metabolized to form some inflammatory and thrombogenic molecules. High levels of sPLA2 can lead to a variety of inflammatory diseases. Furthermore, sPLA2 activity contributes to the formation of epidermal barrier and homeostasis in vivo through the production of free fatty acids. Meanwhile, this is necessary for the formation of lamellar membrane and acidification of stratum corneum (SC). Here, Let’s study a potent secretory non-pancreatic phospholipase A2 (sPLA2) inhibitor, LY-311727.
LY-311727 is a potent secretory non-pancreatic phospholipase A2 (sPLA2) inhibitor.
First of all, LY-311727 is a potent sPLA2 inhibitor, with a Xi(50) of 1.9×105 (chromogenic assay). Nonetheless, sPLA2 is an important proinflammatory enzyme.
In the second place, LY-311727 with 0.1-10 μM suppresses the contractile responses induced by human non-pancreatic PLA2 (hnps-PLA2), in a concentration-related manner. Particularly, LY3-11727 nearly abolishes the hnps-PLA2 responses at 1μM. While it failed to suppress porcine pancreatic PLA2 concentration response curves at the same concentration. Obviously, LY3-11727 displays 1,500-fold selectivity when assayed against porcine pancreatic s-PLA2.
Last but not the least, LY3-11727 with 3-30 mg/kg by i.v. dramatically suppresses the circulating enzyme activity in mice with Mt-sPLA2.
All in all, LY-311727 is a potent secretory non-pancreatic phospholipase A2 (sPLA2) inhibitor.