Small Molecule Drug Targeting of RNA

Targeting at the RNA level is considered as an alternative approach to traditional drug discovery focusing on proteins. The targeting of bacterial ribosomal RNA with aminoglycoside antibiotics has provided clear precedence for the targeting of RNA with small molecule drugs. Aminoglycosides can also bind to human cytoplasmic ribosomal RNA and suppress premature termination codons in human messenger RNAs. This suppression activity is explored for the development of novel therapies for genetic disorders caused by premature stop codon mutations, such as cystic fibrosis and Duchenne muscular dystrophy. While aminoglycosides act on ribosomal RNA, certain small molecule metabolites, including vitamins, lysine and purines, can regulate gene expression by binding to messenger RNA at so-called ‘riboswitches’. Riboswitches consist of complex three-dimensional structures, located in the 5'-untranslated region of bacterial and fungal messenger RNAs, coding for proteins involved in the uptake, biosynthesis and export of these metabolites. It is unknown whether riboswitches also occur in human cells. Riboswitches provide yet another proof that small molecules can influence biological events by binding directly to RNA. The targeting of human messenger RNAs with small synthetic chemical molecules is a relatively new approach, but may create new and unique opportunities for drug discovery. By using messenger RNA as a target, all genes in the human genome may be considered, including those that encode proteins that are not amenable to highthroughput screening, but for which clear associations with disease processes follow from (molecular) genetic or pharmacological investigations. In this area, progress has been made recently in the targeting of the Alzheimer's β- amyloid precursor protein messenger RNA, and the tumor necrosis factor-α messenger RNA.