Novel cell-permeable acyloxymethylketone inhibitors of asparaginyl endopeptidase

Kylie Loak, Dongtao Ni Li, Bénédicte Manoury, Jeremy Billson, Fraser Morton, Ellen Hewitt, Colin Watts

    Research output: Contribution to journalArticlepeer-review

    41 Citations (Scopus)


    Mammalian asparaginyl endopeptidase (AEP) or legumain is a recently identified lysosomal cysteine protease belonging to clan CD. To date it has been shown to be involved in antigen presentation within class II MHC positive cells and in pro-protein processing. Further elucidation of the biological functions of the enzyme will require potent and selective inhibitors and thus we describe here new acyloxymethylketone inhibitors of AEP. The most potent of the series is 2,6-dimethyl-benzoic acid 3-benzyloxycarbonylamino-4-carbamoyl-2-oxo-butyl ester (MV026630) with a kobs/[I] value of 1.09×105 M-1s-1. At low μm concentrations this compound is able to enter living cells and irreversibly inactivate AEP. We show that this results in inhibition of AEP autoactivation and in perturbation of the processing and presentation of T cell epitopes from both tetanus toxin and myelin basic protein.

    Original languageEnglish
    Pages (from-to)1239-1246
    Number of pages8
    JournalBiological Chemistry
    Issue number8
    Publication statusPublished - 20 Aug 2003


    • Antigen processing
    • Asparaginyl endopeptidase
    • Inhibitor

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Clinical Biochemistry


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