title: Rationally designed small molecules that target both the DNA and RNA causing myotonic dystrophy type 1.
abstract: 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 (CTG(exp)) in the DMPK gene. The resultant expanded CUG transcript (CUG(exp)) 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 CTG(exp) and inhibit formation of the CUG(exp) transcript, (2) bind CUG(exp) and inhibit sequestration of MBNL1, and (3) cleave CUG(exp) in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUG(exp) in DM1 model cells, and one reverses two separate CUG(exp)-induced phenotypes in a DM1 Drosophila model.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Lien
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Long M
authors.initials: LM
authors.lastname: Luu
authors.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong , Shatin N.T., Hong Kong, SAR.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Julio F
authors.initials: JF
authors.lastname: Serrano
authors.affiliation: Laboratory of Drosophila Research and School of Life Sciences, The Chinese University of Hong Kong , Shatin N.T., Hong Kong, SAR.
authors.forename: H Y Edwin
authors.initials: HY
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zimmerman
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects* / Q000235:genetics
chemical_list: D054852:Small Molecule Libraries; D012313:RNA; D004247:DNA