Current AIDS treatments are largely directed against the enzymatic activities of reverse transcriptase or protease. Because of the limitations of these inhibitors, there remains a great need to develop alternative therapeutics that target other essential viral activities. This application, a collaborative effort between investigators at University of Virginia and investigators at Message Pharmaceuticals, proposes to further explore HIV Rev as a therapeutic target. The experiments include further analysis of previously identified Rev inhibitors, as well as the development of a high throughput cell-based screen that will enable the identification of novel inhibitors. This screen will be utilized to probe the specialized chemical libraries of Message Pharmaceuticals comprising nearly 150,000 compounds. The compounds have been selected to have properties that would be expected to target RNA and RNA-protein interactions. Potential Rev inhibitors will be sent to the University of Virginia for further characterization and testing, where the compounds will for tested for their ability to inhibit HIV replication. Assays will also be performed to determine where the inhibitor acts in the Rev export pathway. At the end of this project we expect to have a series of compounds inhibiting various steps in the Rev pathway. These compounds should be useful as potential leads in the development of anti-HIV drugs and also as tools to further elucidate the Rev export pathway.
| Shuck-Lee, Deidra; Chang, Hua; Sloan, Emily A et al. (2011) Single-nucleotide changes in the HIV Rev-response element mediate resistance to compounds that inhibit Rev function. J Virol 85:3940-9 |
| Ward, Alex M; Rekosh, David; Hammarskjold, Marie-Louise (2009) Trafficking through the Rev/RRE pathway is essential for efficient inhibition of human immunodeficiency virus type 1 by an antisense RNA derived from the envelope gene. J Virol 83:940-52 |
| Shuck-Lee, Deidra; Chen, Fei Fei; Willard, Ryan et al. (2008) Heterocyclic compounds that inhibit Rev-RRE function and human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 52:3169-79 |
