Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors |
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Authors: | Janina Schmitz Norbert Furtmann Moritz Ponert Dr Maxim Frizler Dr Reik Löser Prof Dr Ulrike Bartz Prof Dr Jürgen Bajorath Prof Dr Michael Gütschow |
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Affiliation: | 1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany);2. Department of Natural Sciences, University of Applied Sciences Bonn‐Rhein‐Sieg von‐Liebig‐Stra?e 20, 53359 Rheinbach (Germany);3. Department of Life Science Informatics, B‐IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstra?e 2, 53113 Bonn (Germany);4. Helmholtz‐Zentrum Dresden‐Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstra?e 400, 01328 Dresden (Germany) |
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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. |
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Keywords: | 3D activity landscapes cysteine proteases human cathepsins nitrile inhibitors |
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