Approaches to the assembly of potent therapeutic agents for the treatment of myotonic dystrophy

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is an incurable neuromuscular disease. DM1 is caused by an expansion of the CTG repeat, whose RNA transcript sequesters the MBNL1 protein into nuclear foci, leading to the misregulation of various pre-mRNAs. Based on a published x-ray structure of a r(CUG)6 hairpin, a benzamidinium ligand was rationally designed and found to selectively bind rCUG repeats and inhibit the MBNL1-rCUGexp interaction with a low micro-molar inhibition potency. Thus, this bisamidinium RNA groove binder represented one of the most promising lead compounds for DM1 treatment. The development of the bisamidinium analogs containing functional substituents will be discussed in Chapter 2. Chapter 3 describes the development of a bisamidinium dimeric ligand as a possible compound for the treatment of DM1. This ligand reveals both the promise and challenge for the small molecule approach. The agent is a potent inhibitor of the MBNL1-rCUGexp both in vitro and in DM1 model cells, and is able to improve two distinct disease phenotypes in a DM1 Drosophila model. However, its relatively low maximum tolerated dose in mice and limited cell uptake provide insights into directions for future development. In addition, a powerful selection method that uses the target DNA or RNA to select their own binders will be discussed in Chapter 4. Compounds discovered using this method are able to undergo the alkyne-azide cycloaddition on the target DNA and RNA. The selectivity of these compounds along with their click products to other DNA/RNA sequences can also be readily accessed. The click products formed have better efficacy and can be used as multi-target agents