Screening for novel small molecule binders of RNA repeat expansions

RNA performs a number of vital roles in the human cell, such as turning genetic information into proteins in the human body and gene regulation via numerous mechanisms. Therefore, its malfunction may lead to severe diseases such as Huntington’s disease or Myotonic Dystrophy type 1. Huntington’s disease is a rare neurodegenerative disease most likely inherited, and it is caused by the trinucleotide repeat expansion r(CAG)exp in the huntingtin gene (HTT). Myotonic dystrophy type 1 is an untreatable neuromuscular disorder caused by the trinucleotide repeat expansion r(CUG)exp. The biology of healthy or disease-infected cells is usually determined by RNA structures, which are desirable targets for chemical probe and lead compounds. Targeting these RNAs with small molecules provides opportunities to affect their function and therapeutically change many pathologic cellular processes. The purpose of this study is to use a fragment-based approach to find small molecules that bind these two trinucleotides repeat expansions by phenotypic screening that involves a luciferase reporter assay for r(CAG)exp, and a target-based approach involving NMR spectroscopy for r(CUG)exp.