Cathepsin B: Active site mapping with peptidic substrates and inhibitors

Janina Schmitz; Erik Gilberg; Reik Löser; Jürgen Bajorath; Ulrike Bartz; Michael Gütschow

doi:10.1016/j.bmc.2018.10.017

Cathepsin B: Active site mapping with peptidic substrates and inhibitors

Bioorg Med Chem. 2019 Jan 1;27(1):1-15. doi: 10.1016/j.bmc.2018.10.017. Epub 2018 Oct 19.

Authors

Janina Schmitz¹, Erik Gilberg², Reik Löser³, Jürgen Bajorath⁴, Ulrike Bartz⁵, Michael Gütschow⁶

Affiliations

¹ Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, D-53359 Rheinbach, Germany.
² Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstr. 2, D-53113 Bonn, Germany.
³ Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, D-01328 Dresden, Germany.
⁴ Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstr. 2, D-53113 Bonn, Germany.
⁵ Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, D-53359 Rheinbach, Germany.
⁶ Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: [email protected].

PMID: 30473362
DOI: 10.1016/j.bmc.2018.10.017

Abstract

The potential of papain-like cysteine proteases, such as cathepsin B, as drug discovery targets for systemic human diseases has prevailed over the past years. The development of potent and selective low-molecular cathepsin B inhibitors relies on the detailed expertise on preferred amino acid and inhibitor residues interacting with the corresponding specificity pockets of cathepsin B. Such knowledge might be obtained by mapping the active site of the protease with combinatorial libraries of peptidic substrates and peptidomimetic inhibitors. This review, for the first time, summarizes a wide spectrum of active site mapping approaches. It considers relevant X-ray crystallographic data and discloses propensities towards favorable protein-ligand interactions in case of the therapeutically relevant protease cathepsin B.

Keywords: Active site mapping; Cathepsin B; Fluorescence-quenched substrates; Peptidomimetic inhibitors; Substrate specificity.

Publication types

Review

MeSH terms

Animals
Catalytic Domain
Cathepsin B / chemistry*
Crystallography, X-Ray
Cysteine Proteinase Inhibitors / chemistry*
Humans
Kinetics
Ligands
Peptides / chemistry*
Substrate Specificity

Substances

Cysteine Proteinase Inhibitors
Ligands
Peptides
Cathepsin B