E-64c-Hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors

Authors

  • Hanna Radzey,

    1. Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld (Germany)
    2. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen (Germany)
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  • Markus Rethmeier,

    1. Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld (Germany)
    2. Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum (Germany)
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  • Dennis Klimpel,

    1. Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld (Germany)
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  • Maresa Grundhuber,

    1. Institut für Laboratoriumsmedizin, Klinikum der Ludwig-Maximilians-Universität, Nußbaumstr. 20, 80336 München (Germany)
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  • Prof. Dr. Christian P. Sommerhoff,

    1. Institut für Laboratoriumsmedizin, Klinikum der Ludwig-Maximilians-Universität, Nußbaumstr. 20, 80336 München (Germany)
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  • Priv.-Doz. Dr. Norbert Schaschke

    Corresponding author
    1. Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld (Germany)
    • Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, 33615 Bielefeld (Germany)
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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).

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