Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD
| Autor: | Andrei Ursu, Tania F. Gendron, Ilyas Yildirim, Kye Won Wang, Jonathan L. Chen, Shruti Choudhary, Jessica A. Bush, Jared T. Baisden, Yong Jie Zhang, Matthew D. Disney, Leonard Petrucelli |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Biology Molecular Dynamics Simulation 01 natural sciences Biochemistry Article Small Molecule Libraries 03 medical and health sciences medicine Humans Amyotrophic lateral sclerosis Genetics C9orf72 Protein Molecular Structure 010405 organic chemistry Extramural Amyotrophic Lateral Sclerosis RNA General Medicine medicine.disease Small molecule 0104 chemical sciences High-Throughput Screening Assays G-Quadruplexes 030104 developmental biology Frontotemporal Dementia Molecular Medicine Trinucleotide repeat expansion Frontotemporal dementia |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 |
| Popis: | Genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide GGGGCC repeat expansions [r(G(4)C(2))(exp)] within the C9orf 72 gene. In these diseases, neuronal loss occurs through an interplay of deleterious phenotypes, including r(G(4)C(2))(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(G(4)C(2))(exp) folds. Structure−activity relationship (SAR) studies and molecular dynamics (MD) simulations were used to define the molecular interactions formed between CB096 and r(G(4)C(2))(exp) that results in the rescue of disease-associated pathways. Overall, this study reveals a unique structural feature within r(G(4)C(2))(exp) that can be exploited for the development of lead medicines and chemical probes. |
| Databáze: | OpenAIRE |
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