. The investigators have been studying binding of the HIV-1 Rev protein to its viral recognition element (Rev responsive element, RRE) and have identified novel small molecule and protein inhibitors of Rev function.They propose to analyze these inhibitors and to continue to identify and design more potent Rev inhibitors. First, they have found that certain amino glycoside antibiotics, in particular neomycin B, can selectively block Rev binding. They will assess further the ability of neomycin B and new synthetic derivatives to block HIV replication. A major priority will be to continue to analyze the molecular basis of the drug:RNA interaction; they will use chemical protection/interference, in vitro genetic selection and NMR spectroscopy. They have also identified a novel protein inhibitor of Rev function: a selected peptide that binds to the Rev effector domain. They will test the ability of this peptide to block HIV replication. In addition, they propose a series of structure-function experiments that will probe the peptide's mechanism of action. They will use this information to continue to develop more potent Rev inhibitors.
