Analyzing airway inflammation with chemical biology

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

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)
4 Downloads (Pure)

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)569-579
Number of pages11
JournalChemistry & Biology
Volume18
Issue number5
DOIs
Publication statusPublished - 26 May 2011

Bibliographical note

ACKNOWLEDGMENTS
We would like to thank S. Duncan (University of Edinburgh) for her technical
assistance with the murine model of allergic inflammation and S. Jenkins
and D. Ru¨ ckerl for helpful discussions. This work was supported by Asthma
UK, the Medical Research Council UK, and the Wellcome Trust. The authors
declare no competing financial interests

Keywords

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

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