The ultimate goal of this research is to characterize forces that direct RNA folding into tertiary structures, and to use this knowledge to rationally design small antisense oligonucleotides targeted to sites of RNA tertiary structure. This novel approach can lead to the rational design of drugs for a variety of diseases for which RNA is a participant, including AIDS. These studies on RNA tertiary structure formation will also help to provide a foundation for understanding how biological activity is mediated through RNA structure. We have chosen fungi as our model system because of a lack of sufficient treatments for these pernicious human pathogens and because they often contain group I introns similar to the much studied one in Tetrahymena. Tertiary interactions important for self-splicing of a fungal ribosomal RNA group I intron will be identified by the effects of functional group substitutions on the binding strength of exogenous exon variants to the intron. These interactions will then be exploited in the design of small antisense agents (5-6 bases) directed to specifically inhibit group I self-splicing activity of the fungal rRNAs, and hence, prevent ribosomal maturation in the fungi.
