School of Pharmacy, Fudan University, Shanghai 201203, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
Bioorg Chem. 2024 Jan;142:106958. doi: 10.1016/j.bioorg.2023.106958. Epub 2023 Nov 4.
UPLC-TOF-MS/MDF directed phytochemical research of Chloranthus japonicus led to the isolation of 46 lindenane sesquiterpenoid dimers, which included 13 new analogs. Their structures with absolute configurations were elucidated by analysis of spectroscopic data. Fourteen compounds with ester chains significantly decreased PCSK9 protein level in medium of HepG2 cells, especially for compounds 14 and 29 (5 µM) with inhibition rates of 69.0% and 72.8%, respectively. Compound 14 in HepG2 cells was evaluated via DiI-LDL uptake assays and found to increase LDL uptake by upregulating LDLR mRNA and protein level. Meanwhile, 14 decreased the secretion of PCSK9 protein in medium and downregulated intracellular PCSK9 protein and mRNA level. The discovery of these natural small molecule compounds provides a novel structure basis for design PCSK9 regulators, making them a promising lead for development of new lipid-lowering agents.
UPLC-TOF-MS/MDF 导向的金粟兰化学成分研究导致分离出 46 个榄香烯倍半萜二聚体，其中包括 13 个新类似物。通过分析光谱数据阐明了它们的结构和绝对构型。十四种具有酯链的化合物可显著降低 HepG2 细胞培养基中的 PCSK9 蛋白水平，特别是化合物 14 和 29（5µM），抑制率分别为 69.0%和 72.8%。通过 DiI-LDL 摄取实验评估化合物 14 在 HepG2 细胞中的作用，发现它通过上调 LDLR mRNA 和蛋白水平来增加 LDL 的摄取。同时，化合物 14 降低了培养基中 PCSK9 蛋白的分泌，并下调了细胞内 PCSK9 蛋白和 mRNA 水平。这些天然小分子化合物的发现为设计 PCSK9 调节剂提供了新的结构基础，使它们成为开发新型降脂药物的有前途的先导化合物。
