부산대학교 도서관

sn-1-Diacylglycerollipase α (DAGL-α)is the main enzyme responsible for the production of the endocannabinoid2-arachidonoylglycerol in the central nervous system. Glycine sulfonamideshave recently been identified by a high throughput screening campaignas a novel class of inhibitors for this enzyme. Here, we report onthe first structure–activity relationship study of glycinesulfonamide inhibitors and their brain membrane proteome-wide selectivityon serine hydrolases with activity-based protein profiling (ABPP).We found that (i) DAGL-α tolerates a variety of biaryl substituents,(ii) the sulfonamide is required for inducing a specific orientationof the 2,2-dimethylchroman substituent, and (iii) a carboxylic acidis essential for its activity. ABPP revealed that the sulfonamideglycine inhibitors have at least three off-targets, including α/β-hydrolasedomain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dualDAGL-α/ABHD6 inhibitor, which makes this compound a potentiallead for the discovery of new molecular therapies for diet-inducedobesity and metabolic syndrome. [ABSTRACT FROM AUTHOR]