Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.
A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (K(d) = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (K(i) = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)(exp) ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.
Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
Chun-Ho
CH
Wong
Lien
L
Nguyen
Jessie
J
Peh
Long M
LM
Luu
Jeannette S
JS
Sanchez
Stacie L
SL
Richardson
Tiziano
T
Tuccinardi
Ho
H
Tsoi
Wood Yee
WY
Chan
H Y Edwin
HY
Chan
Anne M
AM
Baranger
Paul J
PJ
Hergenrother
Steven C
SC
Zimmerman
D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004330:Drosophila; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009223:Myotonic Dystrophy / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009690:Nucleic Acid Conformation / Q000187:drug effects; D012313:RNA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
D004268:DNA-Binding Proteins; D007093:Imidazoles; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins; C535204:bisamidinium; D012313:RNA