Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects

亚麻黄酮 自然(考古学) 化学 材料科学 物理 药理学 医学 地理 考古
作者
Zhexin Chen,Yuqing Shi,Fang Zhong,Kai Zhang,Furong Zhang,Shenghong Xie,Zhongbin Cheng,Qian Zhou,Yi‐You Huang,Hai‐Bin Luo
出处
期刊:Chinese Chemical Letters [Elsevier]
卷期号:: 109956-109956
标识
DOI:10.1016/j.cclet.2024.109956
摘要

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality rate but effective therapeutics are still lacking. Phosphodiesterase-4 (PDE4) inhibitors were reported to be promising anti-IPF agents. Herein, series of biflavonoids isolated from Selaginella uncinate were found to be PDE4 inhibitors and the most active amentoflavone gave a half maximal inhibitory concentration (IC50) of 12 nmol/L, which was further validated by isothermal titration calorimetry with Kd of 23 nmol/L. Besides, co-crystal structure of PDE4-amentoflavone was determined and gave a different binding pattern from roflumilast with multiple H-bonds between it and key residues such as Asn321/Thr333/Gln369/Gly371. So far, this was the first reported co-crystal structure of amentoflavone with its potential binding target in despite of the extensive investigations of this common natural biflavonoid. Furthermore, amentoflavone exhibited remarkable anti-IPF effects in vivo and in vitro, suggesting it as a novel anti-fibrotic agent by targeting PDE4.
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