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Analyzing airway inflammation with chemical biology

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

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

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Original languageEnglish
Number of pages11
JournalChemistry & Biology
Journal publication date27 May 2011


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.


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