Reversible Small Molecule–Nucleic Acid Interactions

Abstract

Historically, small molecules have targeted double helical DNA through intercalation and minor groove complexes. Initially, small molecules to target RNA were focused on RNAs involved in protein biosynthesis. Now, many more compounds to target diverse RNA structures have been designed or discovered. This coincides with the exciting discovery that, while only a small amount of the genome is transcribed into RNA for protein synthesis, much of the genome is used to synthesize a variety of non-coding RNAs (ncRNAs). These have important cell functions, including the involvement of ncRNAs in disease development when they undergo mutation, moreover, their dysregulation has been found to be relevant not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases. Although it has been known for some time that four guanine bases can associate into a tetraplex, our knowledge of how these tetraplexes associate into a variety of four-stranded DNA quadruplexes has greatly advanced. A wide variety of biological functions for these quadruplexes have been discovered. They have a major role in cancer that makes them exciting targets for development of new anticancer agents. At the beginning of our search for new small molecule targets a key structure are the four-way junction and other junction types. The design of new agents to attack these targets will provide many new insights into molecular recognition studies of nucleic acids. The new compounds generated will help us to define the cellular functions of nucleic acid structures and will provide new ideas for the development of nucleic-acid targeted therapeutics.