A novel aurone RNA CAG binder inhibits the huntingtin RNA-protein interaction

Huntington's disease (HD) is a devastating, incurable condition whose pathophysiological mechanism relies on mutant RNA CAG repeat expansions. Aberrant recruitment of RNA-binding proteins by mutant CAG hairpins contributes to the progress of neurodegeneration. In this work, we identified a nove...

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Bibliographic Details
Published in:MedChemComm 2024-09, Vol.15 (9), p.392-396
Main Authors: Ballarin, Giovanna, Biasiotto, Maddalena, Reisbitzer, Annika, Hegels, Marlen, Bolte, Michael, Krauß, Sybille, Berdnikova, Daria V
Format: Article
Language:English
Subjects:
Binding
Chemistry
Gene sequencing
Huntingtin
Huntington's disease
MID1 protein
mRNA
Mutants
Neurodegeneration
Polyglutamine
Proteins
RNA-binding protein
Trinucleotide repeat diseases
Trinucleotide repeats
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Summary:Huntington's disease (HD) is a devastating, incurable condition whose pathophysiological mechanism relies on mutant RNA CAG repeat expansions. Aberrant recruitment of RNA-binding proteins by mutant CAG hairpins contributes to the progress of neurodegeneration. In this work, we identified a novel binder based on an aurone scaffold that reduces the level of binding of HTT mRNA to the MID1 protein in vitro . The obtained results introduce aurones as a novel platform for the design of functional ligands for disease-related RNA sequences. A novel aurone binder for CAG RNA repeats has been identified from a library of twenty-eight compounds. The ligand inhibits toxic RNA-protein interactions in the Huntington's disease model.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d4md00403e