期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 3, 页码 987-1001出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01154
关键词
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资金
- National Key R&D Program of China [2017YFD0200501]
- National Natural Science Foundation of China [31830076]
- Shenzhen Science and Technology Program [KQTD20180411143628272]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from Japan Agency for Medical Research and Development (AMED) [JP18am0101082]
Chitinases not only play vital roles in the human innate immune system but are also essential for the development of pathogenic fungi and pests. Chitinase inhibitors are efficient tools to investigate the elusive role of human chitinases and to control pathogens and pests. Via hierarchical virtual screening, we have discovered a series of chitinase inhibitors with a novel scaffold that have high inhibitory activities and selectivities against human and insect chitinases. The most potent human chitotriosidase inhibitor, compound 40, exhibited a K-i of 49 nM, and the most potent inhibitor of the insect pest chitinase Of Chi-h, compound 53, exhibited a K-i of 9 nM. The binding of these two most potent inhibitors was confirmed by X-ray crystallography. In a murine model of bleomycin-induced pulmonary fibrosis, compound 40 was found to suppress the chitotriosidase activity by 60%, leading to a significant increase in inflammatory cells and suggesting that chitotriosidase played a protective role.
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