Developing potential drugs for the treatment of myotonic dystrophy: from rational design to lead development
Myotonic dystrophy (DM) is currently an incurable genetic disease that affects 1 in 8,000 humans worldwide. Although extensive efforts have been made to understand its pathogenesis, the mechanism by which DM causes its symptoms is not fully understood. Nevertheless, it is known that the alternative splicing regulator, MBNL1, is sequestered by two types of abnormally long RNAs. Specifically there are the tri- and tetra-nucleotide repeats, CUG and CCUG, in DM1 and DM2, respectively. This key discovery inspired the development of ligands that inhibit MBNL1-RNA complex formation, allowing MBNL1 to resume its biological functions. The background to the DM disease will be given in Chapter 1. In 2009, our group reported a rationally designed ligand (11) that recognizes the base mismatches in CUG repeats found in type 1 myotonic dystrophy (DM1). Although little was known about the binding mode, this lead compound disrupts the MBNL1-RNA complex in vitro. Attempts to obtain a crystal of the RNA-ligand complex for X-ray analysis were unsuccessful. As part of an alternative strategy, we have synthesized a small library of lead-like compounds to better understand the structure-activity relationship. In Chapter 2, possible binding modes of the lead ligands are elucidated using a combination of synthesis, gel shift assay, and molecular dynamics simulation. During the course of study, a lead compound for the type 2 myotonic dystrophy (DM2) was discovered. The synthesis, biophysical studies, and in vitro activity of this compound is described in Chapter 3. A new class of potential DM drugs has been discovered using a reported structure of a HIV RNA-ligand complex, combined with the knowledge gained in studying ligand 11. These ligands possess better aqueous solubility and lower toxicity. More importantly, they are shown to be active in a DM1 Drosophila model. The design, synthesis, and evaluation of these ligands are described in Chapter 4.
Myotonic Dystrophy, MBNL1, Inhibition, RNA Repeats, Small Molecules
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign