Inhibition of HIV-1 Rev−RRE Interaction by Diphenylfuran Derivatives
1996; American Chemical Society; Volume: 35; Issue: 42 Linguagem: Inglês
10.1021/bi960954v
ISSN1943-295X
AutoresLynda Ratmeyer, Maria L. Zapp, Michael R. Green, Ravi Vinayak, Arvind Kumar, David W. Boykin, W. David Wilson,
Tópico(s)DNA and Nucleic Acid Chemistry
ResumoThe interactions between RNA structures, such as RRE in the HIV-1 genome, and proteins, such as Rev of HIV-1, are essential for efficient viral replication. Compounds that bind specifically to such RNAs and disrupt their protein complexes offer a novel mechanism for inhibition of replication of the virus. As a step in this approach, we have designed and characterized a series of synthetic diphenylfuran cations that selectively inhibit Rev binding to RRE. Fluorescence titrations and gel band-shift results indicate that the diphenylfurans bind to RRE and inhibit Rev complex formation in a structure-dependent manner. The derivative with the greatest affinity for RRE has an association constant of greater than 10(7) M-1 and inhibits formation of the Rev--RRE complex at concentrations below 1 microM. It binds to RRE considerably more strongly than it binds to simple RNA duplexes. Spectral changes and energy transfer results on complex formation suggest that the compound has a nonclassical intercalation binding mode. CD studies with modified RRE hairpins indicate that the active diphenylfurans bind at the structured internal loop of RRE and cause a conformational change. The most active diphenylfurans are tetracations that appear to bind to RRE by a threading intercalation mode and cause a conformational change in the RNA that is essential for inhibition of Rev complex formation with RRE.
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