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Active Site Mapping of Human Cathepsin F With Dipeptide Nitrile Inhibitors

Active Site Mapping of Human Cathepsin F With Dipeptide Nitrile Inhibitors

Janina Schmitz, Norbert Furtmann, Moritz Ponert, Maxim Frizler, Reik Löser, Ulrike Bartz, Jürgen Bajorath, Michael Gütschow

ChemMedChem. 2015 Aug;10(8):1365-77.

PMID: 26119278

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42412609	Cathepsin F Active human			Price

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