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 X_i(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-PLA_2.

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.

References:

R W Schevitz, et al. Nat Struct Biol. 1995 Jun;2(6):458-65.