期刊
CHEMISTRY & BIOLOGY
卷 18, 期 5, 页码 569-579出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2011.02.017
关键词
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资金
- Asthma UK
- Medical Research Council UK
- Wellcome Trust
- MRC [G0900138, G0600818] Funding Source: UKRI
- Asthma UK [06/057] Funding Source: researchfish
- Medical Research Council [G0600818, G0900138] Funding Source: researchfish
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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