Aristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes = 식물 천연물 유래 DYRK1A 억제물질 aristolactam BIII의 다운증후군 개선효능
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- Aristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes = 식물 천연물 유래 DYRK1A 억제물질 aristolactam BIII의 다운증후군 개선효능
- Miri Choi; Ae-Kyeong Kim; Youngwook Ham; J Y Lee; Daeyong Kim; Ansook Yang; Min Ju Jo; E Yoon; J N Heo; S B Han; M H Ki; Kyu-Sun Lee; Sungchan Cho
- Bibliographic Citation
- Phytomedicine, vol. 92, pp. 153695-153695
- Publication Year
- Purpose: This study aims to identify a novel DYRK1A inhibitor and validate its therapeutic potential in DS-related pathological conditions.
Study design: In order to identify a novel DYRK1A inhibitor, we carried out two-step screening: a structure-based virtual screening of > 300,000 chemical library (first step) and cell-based nuclear factor of activated T-cells (NFAT)-response element (RE) promoter assay (second step). Primary hits were evaluated for their DYRK1A inhibitory activity using in vitro kinase assay and Tau phosphorylation in mammalian cells. Confirmed hit was further evaluated in pathological conditions including DYRK1A-overexpressing fibroblasts, flies, and mice.
Results: We identified aristolactam BIII, a natural product derived from herbal plants, as a novel DYRK1A inhibitor. It potently inhibited the kinase activity of DYRK1A in vitro (IC50 = 9.67 nM) and effectively suppressed DYRK1A-mediated hyperphosphorylation of Tau in mammalian cells. Aristolactam BIII rescued the proliferative defects of DYRK1A transgenic (TG) mouse-derived fibroblasts and neurological and phenotypic defects of DS-like Drosophila models. Oral administration of aristolactam BIII acutely suppressed Tau hyperphosphorylation in the brain of DYRK1A TG mice. In the open field test, aristolactam BIII significantly ameliorated the exploratory behavioral deficit of DYRK1A TG mice.
Conclusion: Our work revealed that aristolactam BIII as a novel DYRK1A inhibitor rescues DS phenotypes in cells and in vivo and suggested its therapeutic potential for the treatment of DYRK1A-related diseases.
- Down syndromeDYRK1AKinaseSmall-molecule inhibitorAristolactam BIII
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- Division of Research on National Challenges > Bionanotechnology Research Center > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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