Download MendeleyAnalyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor.
Sutherland, T.E., Andersen, O.A., Betou, M., Eggleston, I.M., Maizels, R.M., van Aalten, D., Allen, J.E.(2011) Chem Biol 18: 569-579
- PubMed: 21609838
- DOI: https://doi.org/10.1016/j.chembiol.2011.02.017
- Primary Citation of Related Structures:
2YBT, 2YBU - PubMed 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.
Organizational Affiliation:
Centre for Immunity, Infection and Evolution, and the Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Scotland, UK.
