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 Ki of 49 nM, and the most potent inhibitor of the insect pest chitinase OfChi-h, compound 53, exhibited a Ki 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.

中文翻译：

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一系列带有双嘧啶-嘧啶骨架的化合物，可作为新型人类和害虫几丁质酶抑制剂。

几丁质酶不仅在人类先天免疫系统中起着至关重要的作用，而且对于病原性真菌和害虫的发展也至关重要。几丁质酶抑制剂是研究人类几丁质酶难以捉摸的作用以及控制病原体和害虫的有效工具。通过分级虚拟筛选，我们发现了一系列具有新型支架的几丁质酶抑制剂，它们对人和昆虫几丁质酶具有很高的抑制活性和选择性。最有效的人壳三糖苷酶抑制剂化合物40的Ki值为49 nM，而最有效的化合物Chi-h害虫几丁质酶抑制剂53的Ki值为9 nM。通过X射线晶体学证实这两种最有效的抑制剂的结合。在博来霉素诱导的肺纤维化的小鼠模型中，