A Multifunctional Protease Inhibitor To Regulate Endolysosomal Function

Sander I. van Kasteren, Ilana Berlin, Jeff D. Colbert, Doreen Keane, Huib Ovaa, Colin Watts (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    16 Citations (Scopus)

    Abstract

    Proteases constitute a major class of drug targets. Endosomal, compartments harbor several protease families whose attenuation maybe beneficial to a number of biological processes, including inflammation, cancer metastasis, antigen presentation,. and parasite clearance. As a step toward the goal of generalized but targeted protease inhibition in the endocytic pathway, we describe here the synthesis, characterization, and cellular application of a novel multifunctional protease inhibitor. We show that pepstatin A, a potent but virtually insoluble inhibitor of cathepsins D and E, can be conjugated to a single site on cystatin C, a potent inhibitor of the papain-like cysteine proteases (PLCP) and of asparagine endopeptidease (AEP), to create a highly soluble compound capable of suppressing the activity of all 3 principal protease families found in endosomes and lysosomes. We demonstrate that this cystatin-pepstatin inhibitor (CPI) can be taken up by cells to modulate protease activity and affect biological responses.

    Original languageEnglish
    Pages (from-to)1198-1204
    Number of pages7
    JournalACS Chemical Biology
    Volume6
    Issue number11
    DOIs
    Publication statusPublished - Nov 2011

    Keywords

    • LYSOSOMAL CYSTEINE PROTEASES
    • CATHEPSIN-D
    • ANTIGEN PRESENTATION
    • ASPARTIC PROTEASE
    • PEPSTATIN
    • RECEPTOR
    • CYSTATINS
    • ENDOPEPTIDASE
    • CONJUGATE
    • LEGUMAIN

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