Strategies for the Design of Drugs Targeting RNA and RNA-Protein Complexes

In many steps of gene replication and expression, RNA molecules participate as key players, which renders them attractive targets for therapeutic intervention. While the function of nucleic acids as carriers of genetic material is based on their sequence, a number of important RNAs are involved in processes that depend on the defined three-dimensional structures of these molecules. As for proteins, numerous complex folds of RNA exist. The development of drugs that bind specifically to RNA folds opens exciting new ways to expand greatly the existing repertoire of protein-targeted therapeutics. Most functions of RNAs involve interactions with proteins that contain RNA-binding domains. Effector molecules targeted at RNA may either alter the functional three-dimensional structure of the nucleic acid, so the interaction with proteins is thereby inhibited or enhanced, or, as interface inhibitors, they may directly prevent the formation of competent RNA-protein complexes. While the same tools used for the design of protein-targeted drugs may be considered for studying effectors binding to nucleic acids, the differences between proteins and RNAs in the forces which dominate their three-dimensional folding call for novel drug design strategies. In the present review, I will outline how our rapidly expanding knowledge of RNA three-dimensional structure and function facilitates rational approaches to develop RNA-binding compounds. Putative RNA targets for therapeutic intervention will be discussed along with recent advances in understanding RNA-small molecule and RNA-protein interactions.