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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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Authors

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

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Info

Original languageEnglish
Pages569-579
Number of pages11
JournalChemistry & Biology
Journal publication date27 May 2011
Volume18
Issue5
DOIs
StatePublished

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.

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