Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.
RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA.
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way #3A1, Jupiter, FL 33458, USA. Electronic address: Disney@scripps.edu.
Matthew D
MD
Disney
D000818:Animals; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics; D012313:RNA / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid
D004791:Enzyme Inhibitors; D012313:RNA