Click-generated triazole ureas as ultrapotent in vivo–active serine hydrolase inhibitors

摘要: Serine hydrolases are a diverse enzyme class representing ∼1% of all human proteins. The biological functions most serine remain poorly characterized owing to lack selective inhibitors probe their activity in living systems. Here we show that substantial number can be irreversibly inactivated by 1,2,3-triazole ureas, which negligible cross-reactivity with other protein classes. Rapid lead optimization click chemistry-enabled synthesis and competitive activity-based profiling identified ureas selectively inhibit enzymes from branches the hydrolase class, including peptidases (acyl-peptide hydrolase, or APEH), lipases (platelet-activating factor acetylhydrolase-2, PAFAH2) uncharacterized (α,β-hydrolase-11, ABHD11), exceptional potency cells (sub-nanomolar) mice (<1 mg kg(-1)). We APEH inhibition leads accumulation N-acetylated proteins promotes proliferation T cells. These data indicate pharmacologically privileged chemotype for inhibition, combining broad across tunable selectivity individual enzymes.