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

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Original languageEnglish
Pages (from-to)569-79
Number of pages11
JournalChemistry and Biology
Volume18
Issue number5
DOIs
Publication statusPublished - 2011

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.

    Research areas

  • 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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