Developing bivalent ligands to target CUG triplet repeats, the causative agent of myotonic dystrophy type 1

  • Jahromi A
  • Fu Y
  • Miller K
 et al. 
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An expanded CUG repeat transcript (CUG(exp)) is the causative agent of myotonic dystrophy type 1 (DM1) by sequestering muscleblind-like 1 protein (MBNL1), a regulator of alternative splicing. On the basis of a ligand (1) that was previously reported to be active in an in vitro assay, we present the synthesis of a small library containing 10 dimeric ligands (4-13) that differ in length, composition, and attachment point of the linking chain. The oligoamino linkers gave a greater gain in affinity for CUG RNA and were more effective when compared to oligoether linkers. The most potent in vitro ligand (9) was shown to be aqueous-soluble and both cell- and nucleus-permeable, displaying almost complete dispersion of MBNL1 ribonuclear foci in a DM1 cell model. Direct evidence for the bioactivity of 9 was observed in its ability to disperse ribonuclear foci in individual live DM1 model cells using time-lapse confocal fluorescence microscopy.

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  • Anne BarangerUniversity of California - Berkeley

  • Amin Haghighat Jahromi

  • Yuan Fu

  • Kali A. Miller

  • Lien Nguyen

  • Long M. Luu

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