Active Site Mapping of Human CathepsinF with Dipeptide Nitrile Inhibitors

Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex classII. CathepsinS is the major processing enzyme of the invariant chain, but cathepsinF acts in macrophages as its functional synergist which is as potent as cathepsinS in invariant chai...

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Published in:ChemMedChem 2015-08, Vol.10 (8), p.1365
Main Authors: Schmitz, Janina, Furtmann, Norbert, Ponert, Moritz, Frizler, Maxim, Loser, Reik, Bartz, Ulrike, Bajorath, Jurgen, Gutschow, Michael
Format: Article
Language:English
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Summary:Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex classII. CathepsinS is the major processing enzyme of the invariant chain, but cathepsinF acts in macrophages as its functional synergist which is as potent as cathepsinS in invariant chain cleavage. Dedicated low-molecular-weight inhibitors for cathepsinF 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 cathepsinF. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsinsF, 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 cathepsinF, with Ki values
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201500151