Citation: Zhexin Chen, Yuqing Shi, Fang Zhong, Kai Zhang, Furong Zhang, Shenghong Xie, Zhongbin Cheng, Qian Zhou, Yi-You Huang, Hai-Bin Luo. Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects[J]. Chinese Chemical Letters, ;2025, 36(4): 109956. doi: 10.1016/j.cclet.2024.109956 shu

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

Zhexin Chen ^{a, 1} ,
Yuqing Shi ^{a, c, 1} ,
Fang Zhong ^a ,
Kai Zhang ^{a, c} ,
Furong Zhang ^{a, c} ,
Shenghong Xie ^a ,
Zhongbin Cheng ^a ,
Qian Zhou ^{a, *,} ,
Yi-You Huang ^{a, *,} ,
Hai-Bin Luo ^{a, b, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
Song Li’ Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Sanya 572000, China
c.
School of Life and Health Sciences, Hainan University, Haikou 570228, China

zhouqian@hainanu.edu.cn

hyyou@hainanu.edu.cn

hbluo@hainanu.edu.cn

Received Date: 15 March 2024
Revised Date: 26 April 2024
Accepted Date: 30 April 2024
Available Online: 1 May 2024

Figures(5)

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 K_d 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.
- Phosphodiesterase-4,
- Inhibitor,
- Amentoflavone,
- Crystal structure,
- IPF
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