期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 19, 页码 12825-12837出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00654
关键词
-
资金
- National Key R & D Program of China [2018YFA0903200]
- Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangdong) [SMSEGL20SC01]
- General Research Found from the Research Grants Council of HKSAR government [16100722]
- HKSAR government [C6026-19G-A]
- Key Special Project for Introduced Talents Team of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) [GML2019ZD0409]
- National Natural Science Foundation of China [32071188]
- Hong Kong Special Administrative Region [16103719, 16101120, 16101121, SZSTI19SC02, SMSEGL20SC01-H, AoE/M-403-16, AoE/M-401/20, VPRDO19RD03-6]
- Guangdong Basic and Applied Basic Research Foundation [2020A1515010034]
This study identified three first-in-class marine natural products, cA, cB, and cC, which selectively bind to G4C2 G4s and show remarkable bioactivities. Particularly, cA and cC can reduce cell death caused by G4C2 EHR and improve pathological features of related diseases.
The G-quadruplex (G4) forming C9orf72 GGGGCC (G4C2) expanded hexanucleotide repeat (EHR) is the predominant genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Developing selective G4-binding ligands is challenging due to the conformational polymorphism and similarity of G4 structures. We identified three first-in-class marine natural products, chrexanthomycin A (cA), chrexanthomycin B (cB), and chrexanthomycin C (cC), with remarkable bioactivities. Thereinto, cA shows the highest permeability and lowest cytotoxicity to live cells. NMR titration experiments and in silico analysis demonstrate that cA, cB, and cC selectively bind to DNA and RNA G4C2 G4s. Notably, cA and cC dramatically reduce G4C2 EHR-caused cell death, diminish G4C2 RNA foci in (G4C2)(29)-expressing Neuro2a cells, and significantly eliminate ROS in HT22 cells. In (G4C2)(29)-expressing Drosophila, cA and cC significantly rescue eye degeneration and improve locomotor deficits. Overall, our findings reveal that cA and cC are potential therapeutic agents deserving further clinical study.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据