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


Reference:

Sutherland, T. E., Andersen, O. A., Betou, M., Eggleston, I. M., Maizels, R. M., van Aalten, D. and Allen, J. E., 2011. Analyzing airway inflammation with chemical biology: Dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chemistry & Biology, 18 (5), pp. 569-579.

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    Official URL:

    http://dx.doi.org/10.1016/j.chembiol.2011.02.017

    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.

    Details

    Item Type Articles
    CreatorsSutherland, T. E., Andersen, O. A., Betou, M., Eggleston, I. M., Maizels, R. M., van Aalten, D. and Allen, J. E.
    DOI10.1016/j.chembiol.2011.02.017
    DepartmentsFaculty of Science > Pharmacy & Pharmacology
    RefereedYes
    StatusPublished
    ID Code24596

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