title: E-64c-hydrazide: a lead structure for the development of irreversible cathepsin C inhibitors.
abstract: Cathepsin C is a papain-like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule-associated serine proteases. Its exopeptidase activity is structurally explained by the so-called exclusion domain, which blocks the active-site cleft beyond the S2 site and, with its Asp 1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c) (k2/Ki =140±5 M(-1)  s(-1)) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp 1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1'-S2' area with its leucine-isoamylamide moiety. Furthermore, structure-activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n-butyl derivative was identified as the most potent inhibitor of the series (k2/Ki =56 000±1700 M(-1)  s(-1)).
authors.affiliation: Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Radzey
authors.forename: Markus
authors.initials: M
authors.lastname: Rethmeier
authors.forename: Dennis
authors.initials: D
authors.lastname: Klimpel
authors.forename: Maresa
authors.initials: M
authors.lastname: Grundhuber
authors.forename: Christian P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: Norbert
authors.initials: N
authors.lastname: Schaschke
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006834:Hydrazines / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006834:Hydrazines; D011480:Protease Inhibitors; C029424:hydrazine; C032425:N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine; D020789:Cathepsin C; D007930:Leucine
keywords: E-64; cathepsin C; dipeptidyl peptidase I (DPPI); hydrazines; papain-like cysteine proteases; structure-activity relationships