title: Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor.
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.
authors: Centre for Immunity, Infection and Evolution, and the Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Scotland, UK.
authors: Tara E
authors: TE
authors: Sutherland
authors: Ole A
authors: OA
authors: Andersen
authors: Marie
authors: M
authors: Betou
authors: Ian M
authors: IM
authors: Eggleston
authors: Rick M
authors: RM
authors: Maizels
authors: Daan
authors: D
authors: van Aalten
authors: Judith E
authors: JE
authors: Allen
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