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

  • ACS Chem Biol. 2020 Dec 18;15(12):3112-3123. doi: 10.1021/acschembio.0c00049.
Andrei Ursu  1 ,  Kye Won Wang  2 ,  Jessica A Bush  1 ,  Shruti Choudhary  1 ,  Jonathan L Chen  1 ,  Jared T Baisden  1 ,  Yong-Jie Zhang  3 ,  Tania F Gendron  3 ,  Leonard Petrucelli  3 ,  Ilyas Yildirim  2 ,  Matthew D Disney  1
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
  • 2. Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, Florida 33458, United States.
  • 3. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, Florida 32224, United States.
PMID: 33196168 DOI: 10.1021/acschembio.0c00049
Abstract

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'C G G/3'G G C, 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.

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