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Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors
Author(s) -
Schmitz Janina,
Furtmann Norbert,
Ponert Moritz,
Frizler Maxim,
Löser Reik,
Bartz Ulrike,
Bajorath Jürgen,
Gütschow Michael
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500151
Subject(s) - dipeptide , cathepsin s , cathepsin , nitrile , cathepsin l , chemistry , cathepsin b , biochemistry , active site , stereochemistry , cathepsin a , deubiquitinating enzyme , enzyme , peptide , ubiquitin , gene , organic chemistry
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 K i values <10 n M . 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.