Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD
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https://figshare.com/articles/dataset/Structural_Features_of_Small_Molecules_Targeting_the_RNA_Repeat_Expansion_That_Causes_Genetically_Defined_ALS_FTD/13242546
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资源简介：
Genetically defined amyotrophic lateral
sclerosis (ALS) and frontotemporal
dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide
GGGGCC repeat expansions [r(G4C2)exp] within the C9orf72 gene. In these diseases, neuronal
loss occurs through an interplay of deleterious phenotypes, including
r(G4C2)exp RNA gain-of-function mechanisms.
Herein, we identified a benzimidazole derivative, CB096, that specifically
binds to a repeating 1 × 1 GG internal loop structure, 5′CGG/3′GGC, that is formed
when r(G4C2)exp folds. Structure–activity
relationship (SAR) studies and molecular dynamics (MD) simulations
were used to define the molecular interactions formed between CB096
and r(G4C2)exp that results in the
rescue of disease-associated pathways. Overall, this study reveals
a unique structural feature within r(G4C2)exp that can be exploited for the development of lead medicines
and chemical probes.
创建时间：
2020-11-16
