Research Project
6074549
The ability of ribosomes to maintain the correct translational reading frame is fundamental to the integrity of protein synthesis and to cell growth and viability. However, there are now a number of examples utilized by viruses in which elongating ribosomes are programmed to shift their translational reading frame one base in the 5' direction. This process is called programmed - 1 ribosomal frameshifting. Programmed - 1 ribosomal frameshifting is utilized uniquely by eucaryotic viruses, making it a compelling target for developing antiviral agents. The human immunodeficiency virus type 1 (HIV-1) utilizes a programmed -1 ribosomal frameshift to synthesize both the gag and gag-pol proteins from a single transcript. Using yeast as a model system and subsequently mammalian cells, we have been investigating the cis-acting elements and trans-acting factors that determine programmed - 1 ribosomal frameshifting efficiencies. Using the double-stranded L-A virus system of yeast, we have shown that small changes in the ratio of the gag to gag-pol synthesized by altering frameshifting efficiencies leads to a loss of the killer virus. These findings have led us to develop the concept that antiviral agents can bc identified that alter the efficiency of programmed frameshifting without dramatically affecting global protein synthesis. Based on this reasoning, we searched for and identified compounds that, at concentrations that did not dramatically affect cell growth or translation altered ribosomal frameshifting and promoted reduction of HIV infectivity. Based on these results, our goal is the development of novel HIV therapeutics that targets ribosomal frameshifting and reduces HIV infectivity. PROPOSED COMMERCIAL APPLICATIONS: The goal of this research is the development of new anti-HIV therapeutic agents to treat AIDS. Ribosomal frameshifting is a novel cellular target to develop new drugs. It is now very clear that there is a strong need for additional anti-HIV drugs that attack new targets. Consequently the potential commercial application of these compounds is high.
