Redirecting the Peptide Cleavage Causes Protease Inactivation
Abstract
Abstract Cysteine and serine proteases cleave peptides through covalent catalysis by generating a transient adduct with the N‐terminal part of the substrate after releasing its C‐terminal part. We demonstrate the unique redirection of this event leading to strong enzyme inactivation. For targeting human cathepsin B, a cysteine protease of significant therapeutic importance, we designed tailored peptidomimetics with a variety of dipeptide fragments directed toward the occluding loop and equipped with numerous N‐terminal carbamate warheads. The carbamate deprotonation catalyzed by the active site thiolate initiates the redirected cleavage. The C‐terminal part of the inhibitors remains covalently attached to the protease. Hydrolysis of such carbamoyl‐enzyme complexes is catalytically unsupported rendering inhibition irreversible. This novel mechanism of action comprises a significant extension of the covalent drug space.
Article Details
Authors (21)
Christian Breuer
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Jim Küppers
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Anna‐Christina Schulz‐Fincke
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Anna Heilos
Institute for Physical and Theoretical Chemistry Julius‐Maximilians‐Universität Würzburg Emil‐Fischer‐Str. 42 97074 Würzburg Germany
Carina Lemke
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Petra Spiwoková
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo n. 2 16610 Prague Czech Republic
Janina Schmitz
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Laura Cremer
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Marta Frigolé‐Vivas
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Michael Lülsdorff
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Matthias D. Mertens
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Filip Wichterle
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo n. 2 16610 Prague Czech Republic
Miloš Apeltauer
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo n. 2 16610 Prague Czech Republic
Martin Horn
Erik Gilberg
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany
Norbert Furtmann
Jürgen Bajorath
Ulrike Bartz
Department of Natural Sciences University of Applied Sciences Bonn‐Rhein‐Sieg von‐Liebig‐Str. 20 53359 Rheinbach Germany
Bernd Engels
Institute for Physical and Theoretical Chemistry, Julius-Maximilians-Universität Würzburg, Emil-Fischer-Straße 42, Würzburg 97074, Germany
Michael Mareš
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo n. 2 16610 Prague Czech Republic
Michael Gütschow
Pharmaceutical Institute Pharmaceutical & Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany