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 binders. Small molecules that target viral RNA sites and prevent the formation of pivotal regulatory RNA-protein complexes are promising candidates for antiretroviral drug discovery. 

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