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

Reference:

Sutherland, T. E., Andersen, O. A., Betou, M., Eggleston, I. M., Maizels, R. M., van Aalten, D. and Allen, J. E., 2011. Analyzing airway inflammation with chemical biology: Dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chemistry & Biology, 18 (5), pp. 569-579.

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Official URL:

http://dx.doi.org/10.1016/j.chembiol.2011.02.017

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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