Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases linked to the C9orf72 gene.
• Hexanucleotide repeat expansions (r(G4C2)exp) in the C9orf72 gene are a primary cause of these conditions.
• Neuronal loss in c9ALS/FTD involves toxic RNA gain-of-function mechanisms.

Purpose of the Study:

• To identify small molecules that can bind to and neutralize the toxic r(G4C2)exp RNA.
• To explore the therapeutic potential of targeting specific RNA structures in neurodegenerative diseases.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted to understand how CB096 interacts with the RNA.
• Molecular dynamics (MD) simulations were employed to analyze the binding interactions between CB096 and r(G4C2)exp.
• The effect of CB096 on disease-associated pathways was evaluated.

Main Results:

• A benzimidazole derivative, CB096, was identified as a specific binder to a 1x1 GG internal loop structure within r(G4C2)exp RNA.
• Detailed molecular interactions between CB096 and the RNA structure were elucidated through SAR and MD simulations.
• CB096 demonstrated the ability to rescue disease-associated pathways.

Conclusions:

• The study identified a druggable structural feature within the toxic r(G4C2)exp RNA.
• CB096 represents a promising lead compound for developing novel therapeutics for c9ALS/FTD.
• This work opens avenues for designing chemical probes and medicines targeting RNA structures in neurodegenerative diseases.