Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors |
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Authors: | Adibekian Alexander Martin Brent R Wang Chu Hsu Ku-Lung Bachovchin Daniel A Niessen Sherry Hoover Heather Cravatt Benjamin F |
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Institution: | The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA. |
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Abstract: | Serine hydrolases are a diverse enzyme class representing ~1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. Here we show that a substantial number of serine hydrolases can be irreversibly inactivated by 1,2,3-triazole ureas, which show negligible cross-reactivity with other protein classes. Rapid lead optimization by click chemistry-enabled synthesis and competitive activity-based profiling identified 1,2,3-triazole ureas that selectively inhibit enzymes from diverse branches of the serine hydrolase class, including peptidases (acyl-peptide hydrolase, or APEH), lipases (platelet-activating factor acetylhydrolase-2, or PAFAH2) and uncharacterized hydrolases (α,β-hydrolase-11, or ABHD11), with exceptional potency in cells (sub-nanomolar) and mice (<1 mg kg(-1)). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T cells. These data indicate 1,2,3-triazole ureas are a pharmacologically privileged chemotype for serine hydrolase inhibition, combining broad activity across the serine hydrolase class with tunable selectivity for individual enzymes. |
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