Selective G-Quadruplex-Binding Small Molecules Ameliorate Pathological Signatures of ALS/FTD Models.

The G-quadruplex (G4) forming 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 (), chrexanthomycin B (), and chrexanthomycin C (), with remarkable bioactivities. Thereinto, shows the highest permeability and lowest cytotoxicity to live cells. NMR titration experiments and analysis demonstrate that , , and selectively bind to DNA and RNA G4C2 G4s. Notably, and dramatically reduce G4C2 EHR-caused cell death, diminish G4C2 RNA foci in (G4C2)-expressing Neuro2a cells, and significantly eliminate ROS in HT22 cells. In (G4C2)-expressing , and significantly rescue eye degeneration and improve locomotor deficits. Overall, our findings reveal that and are potential therapeutic agents deserving further clinical study.