Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy with 1 in 8000 people affected. DM1 is caused by an expansion of the CTG repeat sequence in the DMPK gene on chromosome 19q. The normal length of this sequence is 37-50 CTG repeats but >50 means the individual has the disease. At that threshold the CTG repeats are unstable leading to a progressive expansion that can be reach 10,000 triplet repeats. The longer repeats correlate with more severe disease phenotypes. The rCUG transcript is known to be the causative agent of DM1. One approach to treating DM1 is to selectively degrade CUG repeats (CUGexp). Herein, we report readily prepared small molecules that are not only able to inhibit the deleterious interaction of CUGexp and important proteins (for example, MBNL1) but also might lead to a degradation of the toxic RNA. These agents are based on conjugates of the triaminotriazine moiety and an acridine or a bisamidinium unit (ligands 1  and 2  , respectively). These small molecules bind to CUGexp with highly selectivity and disrupt the MBNL1-CUGexp interaction. To develop an agent that has an ability to degrade RNA, we have conjugated these scaffolds to chemically reactive units that induce RNA cleavage. Introducing the cleaving unit to ligands 1  and 2  does not change their binding affinity toward CUGexp. Incubating these new agents with CUG repeat sequences in vitro leads to a disappearance of RNA implicating its degradation. Importantly, treatment of DM1 model cells with these ligands results in a reduction in the (CUG)expmRNA level within the cell.

Small molecules that control the fate of CUG RNA repeats, the causative agent in myotonic dystrophy type 1

248th National Meeting (2014)

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