A Series of Compounds Bearing a Dipyrido-Pyrimidine Scaffold Acting as Novel Human and Insect Pest Chitinase Inhibitors

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.

几丁质酶（Chitinases）不仅在人类先天免疫系统中发挥至关重要的作用，同时对于致病真菌与害虫的生长发育也不可或缺。几丁质酶抑制剂是探究人类几丁质酶尚不明确的功能、以及防控病原与害虫的有效工具。本研究通过层级虚拟筛选（hierarchical virtual screening），发现了一系列具有全新骨架的几丁质酶抑制剂，这类抑制剂对人类与昆虫几丁质酶展现出优异的抑制活性与选择性。其中活性最强的人类壳三糖酶（chitotriosidase）抑制剂——化合物40，其抑制常数Ki值为49 nM；活性最强的害虫几丁质酶OfChi-h抑制剂——化合物53，Ki值为9 nM。这两种强效抑制剂的结合模式已通过X射线晶体衍射法（X-ray crystallography）得以验证。在博莱霉素诱导的肺纤维化小鼠模型中，化合物40可将壳三糖酶活性抑制60%，同时导致炎症细胞数量显著升高，这一结果提示壳三糖酶发挥了保护性作用。