title: Development of small molecule inhibitors and probes of human SUMO deconjugating proteases.
abstract: Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Albrow
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Ponder
authors.forename: Domenico
authors.initials: D
authors.lastname: Fasci
authors.forename: Miklós
authors.initials: M
authors.lastname: Békés
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D001372:Aza Compounds / Q000737:chemistry; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D004852:Epoxy Compounds; D007659:Ketones; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D010450:Endopeptidases; D010447:Peptide Hydrolases; C404512:SENP1 protein, human; C512579:Senp5 protein, human; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human; C408873:SENP6 protein, human; C533959:SENP7 protein, human