A Small Molecule that Binds an RNA Repeat Expansion Stimulates Its Decay via the Exosome Complex

Alicia J. Angelbello, Raphael I. Benhamou, Suzanne G. Rzuczek, Shruti Choudhary, Zhenzhi Tang, Jonathan L. Chen, Madhuparna Roy, Kye Won Wang, Ilyas Yildirim, Albert S. Jun, Charles A. Thornton, Matthew D. Disney

Research output: Contribution to journalArticlepeer-review


Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)exp is harbored in the 3′ untranslated region, and the compound has no effect on the mRNA's abundance. In FECD, however, r(CUG)exp is located in an intron, and the small molecule facilitates excision of the intron, which is then degraded by the RNA exosome complex. Thus, structure-specific, RNA-targeting small molecules can act disease specifically to affect biology, either by disabling the gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).

Original languageEnglish
Pages (from-to)34-45.e6
JournalCell Chemical Biology
Issue number1
StatePublished - 21 Jan 2021


  • RNA
  • RNA splicing
  • chemical biology
  • decay pathways
  • drug discovery
  • microsatellite disorders
  • targeted degradation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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