title: Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases.
abstract: Serine hydrolase inhibitors, which facilitate enzyme function assignment and are used to treat a range of human disorders, often act by an irreversible mechanism that involves covalent modification of the serine hydrolase catalytic nucleophile. The portion of mammalian serine hydrolases for which selective inhibitors have been developed, however, remains small. Here, we show that N-hydroxyhydantoin (NHH) carbamates are a versatile class of irreversible serine hydrolase inhibitors that can be modified on both the staying (carbamylating) and leaving (NHH) groups to optimize potency and selectivity. Synthesis of a small library of NHH carbamates and screening by competitive activity-based protein profiling furnished selective, in vivo-active inhibitors and tailored activity-based probes for multiple mammalian serine hydrolases, including palmitoyl protein thioesterase 1, mutations of which cause the human disease infantile neuronal ceroid lipofuscinosis.
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Armand B
authors.initials: AB
authors.lastname: Cognetta
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hyeon-Cheol
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Martini
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: jhulce@scripps.edu.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hulce
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002219:Carbamates; D015842:Serine Proteinase Inhibitors; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D012697:Serine Endopeptidases