MODULATION OF THE REV-RRE INTERACTION BY AROMATIC HETEROCYCLIC-COMPOUNDS

The HIV-1 Rev protein regulates the nucleocytoplasmic distribution of viral precursor RNAs that encode HIV-I structural proteins. Rev-mediat ed viral RNA expression requires a sequence-specific interaction betwe en Rev and a viral RNA sequence, the Rev responsive element (RRE). Bec ause the Rev-RRE interaction is essential for HIV-1 replication, anti- viral agents that selectively block this interaction may be effective anti-HIV-l therapeutics. Here, we show that certain aromatic heterocyc lic compounds, in particular, a tetracationic diphenylfuran, AK.A, can block binding of Rev to its high-affinity viral RNA binding site. AK. A abolishes Rev-RRE interactions at concentrations as low as 0.1 mu M. Inhibition appears to be selective and results from competitive bindi ng of the drug to a discrete region within the Rev binding site. Inter estingly, the molecular basis for the AK.A-RNA interaction, as well as the mode of RNA binding differs from previously described aminoglycos ide Rev inhibitors. Analysis of a variety of aromatic heterocyclic com pounds and their derivatives reveals stereo-specific features required for the inhibition. Our results further demonstrate the feasibility o f identifying and designing small molecules that selectively block vir al RNA-protein interactions. (C) 1997 Elsevier Science Ltd.