Currently, RNA is significantly underutilized as a potential target for drug development: most likely because there exists a lack of basic knowledge about how one should design a molecule to target a folded RNA. In our research, the RNA-binding properties of sidechain-functionalized polyamines are being examined with two important RNA targets: TAR RNA and RRE RNA of HIV. Molecules that bind to these RNAs can potentially shut down replication of the virus. The basic knowledge that will be developed from this work will ultimately be applicable to other RNA targets, and will provide a general set of guidelines for designing molecules that selectively bind a folded RNA structure. We identified a new version of our molecules that binds extremely well to TAR RNA and blocks association of the tat protein. A collaboration with a cell biology group to study the activity of these molecules in HIV infected cells has demonstrated very good activity. We have completed an extensive study on the antiviral effects of these molecules on peripheral blood mononuclear cells (PBMCs), which are collections of white blood cells containing the CD4 cells that HIV likes to infect. Our molecules have good activity with low toxicity on PBMCs, and our molecules are active across a range of different HIV strains (8 different clades of HIV). A paper on this research has been published. We are continuing to optimize the biological activity of our molecules and we are pursuing fundamental studies to understand the molecular recognition properties of our molecules for TAR RNA. We are also collaborating to investigate whether HIV resistance to our molecules emerges over time. At the same time, we have pursued the development of a small molecule to interfere with nucleocapid protein 7, NCp7, and its association in packaging viral HIV RNA. Interfering with this process is another strategy to interfere with HIV's progression.