PLRP2 Inhibitors

Chemical inhibitors of pancreatic lipase-related protein 2 (PLRP2) are a set of compounds that interfere with the enzyme's ability to hydrolyze fats. Orlistat stands out as a prominent inhibitor, which functions by covalently binding to the serine residue within the active site of PLRP2. This binding disrupts the enzymatic activity, preventing PLRP2 from breaking down dietary fats into smaller molecules that can be absorbed by the body. Similarly, Lipstatin and its saturated form, Tetrahydrolipstatin, act as potent inhibitors by covalently modifying the same serine residue, rendering the enzyme inactive. These chemicals are particularly effective as they form a stable, irreversible bond, ensuring prolonged inhibition of PLRP2.

Other inhibitors, such as Ebelactone A and Ebelactone B, likely inhibit PLRP2 by also targeting its active site. These inhibitors may form a temporary bond with the enzyme, competing with natural lipid substrates, thereby reducing the enzyme's activity. Palmitoyl trifluoromethyl ketone further expands the arsenal of PLRP2 inhibitors by mimicking the enzyme's natural substrates, which could lead to competitive inhibition. By occupying the active site of PLRP2, these analogs prevent the binding and processing of genuine lipid molecules. In the case of JZL 184 and RHC 80267, although primarily known to inhibit other lipases, their inhibition of PLRP2 can be attributed to the structural and mechanistic similarities shared among these enzymes. This suggests that their inhibitory effects on PLRP2 could be due to a blockade of the enzyme's active site, thus reducing its lipid hydrolysis activity. Compounds like CAY10499, URB602, and PF-750, despite being selective towards other types of lipases, can also inhibit PLRP2.