Neomycin-Acridine Conjugate: A Potent Inhibitor of Rev-RRE Binding
Sarah R. Kirk, Nathan W. Luedtke, and Yitzhak Tor
Abstract
Neomycin-acridine conjugate (neo-acridine)
was synthesized by covalently linking neomycin B to 9-aminoacridine via a short
spacer. Neo-acridine was a potent
inhibitor of HIV-1 Rev-Response Element (RRE) binding showing a two order of
magnitude higher affinity for RRE than that of the parent neomycin B. It appears
that neo-acridine is the strongest competitive inhibitor of Rev-RRE binding. It binds the RRE with an inhibition const. of 1.5 nM and
effectively disrupts the Rev-RRE complex. The
affinity of neo-acridine to the RRE is only 2-fold lower than that of the Rev
peptide. These results demonstrate
that (a) small molecules can effectively interfere with protein-RNA
interactions, (b) synthetic ligands can achieve very high RNA affinity,
approaching that of the natural RNA-binding domains on proteins, and (c) the
combination of different binding modes (e.g., ionic and intercalation) is a
powerful approach for enhancing the RNA affinity of synthetic
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