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-1 structural proteins. Rev-mediated viral RNA expression requires a sequence-specific interaction between Rev and a viral RNA sequence, the Rev responsive element (RRE). Because the Rev-RRE interaction is essential for HIV-1 replication, anti-viral agents that selectively block this interaction may be effective anti-HIV-1 therapeutics. Here, we show that certain aromatic heterocyclic 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 microM. Inhibition appears to be selective and results from competitive binding of the drug to a discrete region within the Rev binding site. Interestingly, the molecular basis for the AK.A-RNA interaction, as well as the mode of RNA binding differs from previously described aminoglycoside Rev inhibitors. Analysis of a variety of aromatic heterocyclic compounds and their derivatives reveals stereo-specific features required for the inhibition. Our results further demonstrate the feasibility of identifying and designing small molecules that selectively block viral RNA-protein interactions.
Zapp
M L
ML
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester 01605, USA. maria.zapp@ummed.edu
Young
D W
DW
Kumar
A
A
Singh
R
R
Boykin
D W
DW
Wilson
W D
WD
Green
M R
MR
D000617:Aminoglycosides / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D005663:Furans / Q000378:metabolism / Q000494:pharmacology*; D015694:Gene Products, rev / Q000187:drug effects* / Q000378:metabolism*; D015752:Genes, env / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D008969:Molecular Sequence Data; D012326:RNA Splicing; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012367:RNA, Viral / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D054321:rev Gene Products, Human Immunodeficiency Virus
D000617:Aminoglycosides; D019380:Anti-HIV Agents; D005663:Furans; D015694:Gene Products, rev; D012333:RNA, Messenger; D012367:RNA, Viral; D054321:rev Gene Products, Human Immunodeficiency Virus