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 journalArticlepeer-review

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)569-79
Number of pages11
JournalChemistry and Biology
Volume18
Issue number5
DOIs
Publication statusPublished - 2011

Keywords

  • Animals
  • Binding Sites
  • Binding, Competitive
  • Chitinase
  • Computer Simulation
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Eosinophils
  • Female
  • Gene Expression Regulation
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils
  • Pneumonia
  • Protein Structure, Tertiary
  • RNA Interference
  • RNA, Small Interfering
  • Xanthines

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