High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation
| Autor: | Udit J. Sheth, Alexandra B. Sutter, Michael G. Kearse, Sami J. Barmada, Peter K. Todd, Shannon E. Wright, Katelyn M. Green, Brittany N. Flores, Magdalena I. Ivanova |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ataxia Drug Evaluation Preclinical Biology Biochemistry 03 medical and health sciences Eukaryotic translation C9orf72 Tremor medicine Animals Humans Molecular Biology Cells Cultured Genetics DNA Repeat Expansion 030102 biochemistry & molecular biology Circular Dichroism Amyotrophic Lateral Sclerosis Neurodegeneration RNA Neurodegenerative Diseases Translation (biology) Azepines Cell Biology medicine.disease Rats HEK293 Cells Pyrimidines 030104 developmental biology Fragile X Syndrome Ran Quinazolines medicine.symptom Trinucleotide Repeat Expansion Propidium Frontotemporal dementia |
| Zdroj: | Journal of Biological Chemistry. 294:18624-18638 |
| ISSN: | 0021-9258 |
| Popis: | Repeat-associated non-AUG (RAN) translation is a noncanonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X-associated tremor ataxia syndrome (FXTAS), ALS, and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3,253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using CD and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|