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

Andrei Ursu, Kye Won Wang, Jessica A. Bush, Shruti Choudhary, Jonathan L. Chen, Jared T. Baisden, Yong Jie Zhang, Tania F. Gendron, Leonard Petrucelli, Ilyas Yildirim, Matthew D. Disney

Research output: Contribution to journalArticlepeer-review

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′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.

Original languageEnglish (US)
Pages (from-to)3112-3123
Number of pages12
JournalACS Chemical Biology
Volume15
Issue number12
DOIs
StatePublished - Dec 18 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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