AIDSWEEKLY Plus; Monday, September 1, 2003
Staff Medical Writer

"Rev is an essential regulatory HIV-1 protein that binds the Rev responsive element (RRE) within the env gene of the HIV-1 RNA genome, activating the switch between viral latency and active viral replication," researchers in the United States explained.

"Previously, we have shown that selective incorporation of the fluorescent probe 2-aminopurine (2-AP) into a truncated form of the RRE sequence (RRE-IIB) allowed the binding of an arginine-rich peptide derived from Rev and aminoglycosides to be characterized directly by fluorescence methods," noted E.S. DeJong and coauthors at the University of Maryland.

"Using these fluorescence and nuclear magnetic resonance (NMR) methods, proflavine has been identified, through a limited screen of selected small heterocyclic compounds, as a specific and high-affinity RRE-IIB binder which inhibits the interaction of the Rev peptide with RRE-IIB," they wrote in the journal Biochemistry.

"Direct and competitive 2-AP fluorescence binding assays reveal that there are at least two classes of proflavine binding sites on RRE-IIB: a high-affinity site that competes with the Rev peptide for binding to RRE-IIB (K-D similar to 0.1±10.05 microM) and a weaker binding site(s) (K-D similar to 1.1±0.05 microM)," according to the report. "Titrations of RRE-IIB with proflavine, monitored using H-1 NMR, demonstrate that the high-affinity proflavine binding interaction occurs with a 2:1 (proflavine:RRE-IIB) stoichiometry, and NOEs observed in the NOESY spectrum of the 2:1 proflavine(.)RRE-IIB complex indicate that the two proflavine molecules bind specifically and close to each other within a single binding site."

"NOESY data further indicate that formation of the 2:1 proflavine(.)RRE-IIB complex stabilizes base pairing and stacking within the internal purine-rich bulge of RRE-IIB in a manner analogous to what has been observed in the Rev peptide(.)RRE-IIB complex," the investigators added.

"The observation that proflavine competes with Rev for binding to RRE-IIB by binding as a dimer to a single high-affinity site opens the possibility for rational drug design based on linking and modifying it and related compounds," they concluded.

Dejong and colleagues published their study in Biochemistry (Proflavine acts as a Rev inhibitor by targeting the high-affinity Rev binding site of the Rev responsive element of HIV-1. Biochemistry. 2003 Jul 8;42(26):8035-46.

For additional information, contact J.P. Marino, University of Maryland, Maryland Biotechnology Institute, Center for Advanced Research Biotechnology, 9600 Gudelsky Dr., Rockville, MD 20850, USA.

Publisher contact information for the journal Biochemistry is: American Chemical Society, 1155 16th St. NW, Washington, DC 20036, USA.

The information in this article comes under the major subject areas of AIDS & HIV, RNA Research, Pharmaceutical & Drug Development and Virology.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

DeJong ES, Chang CE, Gilson MK, et al. "Proflavine acts as a Rev inhibitor by targeting the high-affinity Rev binding site of the Rev responsive element of HIV-1", Biochemistry. 2003 Jul 8;42(26):8035-46.

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