title: Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors.
abstract: Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low-molecular-weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent-reversible inhibitors, was performed to draw structure-activity relationships for the non-primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N-(4-phenylbenzoyl)-leucylglycine nitrile) and 12 (N-(4-phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with Ki values <10 nM. With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure-activity relationships for this series of cathepsin F inhibitors.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).|Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg von-Liebig-Straße 20, 53359 Rheinbach (Germany).
authors.forename: Janina
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).|Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstraße 2, 53113 Bonn (Germany).
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Moritz
authors.initials: M
authors.lastname: Ponert
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors.forename: Maxim
authors.initials: M
authors.lastname: Frizler
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).|Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden (Germany).
authors.forename: Reik
authors.initials: R
authors.lastname: Löser
authors.affiliation: Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg von-Liebig-Straße 20, 53359 Rheinbach (Germany).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bartz
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstraße 2, 53113 Bonn (Germany).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany). guetschow@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D056646:Cathepsin F / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009570:Nitriles; D020033:Protein Isoforms; D056646:Cathepsin F
keywords: 3D activity landscapes; cysteine proteases; human cathepsins; nitrile inhibitors