The investigator proposes to continue analysis of the molecular basis of small molecules that selectively block the HIV-1 Rev-RRE interaction and Rev function. Attempts will be made to delineate the structure-function characteristics that govern RRE-aminoglycoside binding in vivo, to understand the effects of mutations in RRE that block aminoglycoside-binding on Rev function. These studies will then lead to the question of whether aminoglycoside-resistant RREs can emerge during viral replication and the fitness of such mutants. Furthermore, a newly identified diphenylfuran compound, as an inhibitor of Rev:RRE interacton will be further developed. First, the molecular basis of diphenylfuran:RRE interaction will be studied by a variety of spectroscopic methods, structure-activity relationship study will be performed to evolve compounds that are most effective in blocking viral replication. Finally, using small animal models, in vivo efficacy, pharmacokinetics and toxicity studies will be performed.
