Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor

Tara E. Sutherland, Ole A. Andersen, Marie Betou, Ian M. Eggleston, Rick M. Maizels, Daan van Aalten, Judith E. Allen

    Research output: Contribution to journalArticle

    38 Citations (Scopus)

    Abstract

    Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.

    Original languageEnglish
    Pages (from-to)569-579
    Number of pages11
    JournalChemistry & Biology
    Volume18
    Issue number5
    DOIs
    Publication statusPublished - 27 May 2011

    Keywords

    • Chitotriosidase
    • Asthma
    • Identification
    • Mechanism
    • Tissue
    • Crystallography
    • Allosamidin
    • Eosinophils
    • Activation
    • Proteins

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