Rationally Designed Small Molecules That Target Both the DNA and RNA Causing Myotonic Dystrophy Type 1

Lien Nguyen, Long M. Luu, Shaohong Peng, Julio F. Serrano, H. Y.Edwin Chan, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review


Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTGexp) in the DMPK gene. The resultant expanded CUG transcript (CUGexp) identified as a toxic agent sequesters important proteins, such as muscleblind-like proteins (MBNL), undergoes repeat-associated non-ATG (RAN) translation, and potentially causes microRNA dysregulation. We report rationally designed small molecules that target the DM1 pathobiology in vitro in three distinct ways by acting simultaneously as transcription inhibitors, by inhibiting aberrant protein binding to the toxic RNA, and by acting as RNase mimics to degrade the toxic RNA. In vitro, the agents are shown to (1) bind CTGexp and inhibit formation of the CUGexp transcript, (2) bind CUGexp and inhibit sequestration of MBNL1, and (3) cleave CUGexp in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUGexp in DM1 model cells, and one reverses two separate CUGexp-induced phenotypes in a DM1 Drosophila model.

Original languageEnglish (US)
Pages (from-to)14180-14189
Number of pages10
JournalJournal of the American Chemical Society
Issue number44
StatePublished - Nov 11 2015

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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