Ribonucleic acid (RNA) function is central to all life, including that of viruses and bacteria. Antibacterial agents such as neomycin and erythromycin are examples of existing drugs that target sites in bacterial ribosomal RNAs. Unfortunately, bacteria are becoming increasingly resistant to these compounds via adaptation that allows for the modification of the RNA target or modification of the antibiotic. Human immunodeficiency virus (HIV), adenovirus (AV) and Epstein-Barr virus (EBV) are examples of human pathogens that all have unique RNA structures that appear necessary for replication. Each of these RNAs are potential targets for drug intervention. Unfortunately, our lack of understanding of the recognition of RNA by small molecules limits our ability to design high affinity ligands. The goal of this project is to identify low molecular weight ligands (<-l000 Da) that bind selectively to predefined RNA structures and inhibit the formation of protein-RNA complexes. This will be accomplished via the generation of structurally diverse libraries of molecules and the selection of library members with the requisite affinity and selectivity properties. The libraries are designed to contain intercalating ligands with appended functional groups capable of making specific contacts in the grooves of an RNA double helix. These experiments will ultimately lead to the ability to design and synthesize molecules that bind selectively to specific sequences of duplex RNA. In addition, these new compounds would have the potential to be developed into therapeutics for viral and bacterial infections.
