A tale of two targets: differential RNA selectivity of nucleobase-aminoglycoside conjugates

Aminoglycoside antibiotics are RNA-binding polyamines that can bind with similar affinities to structurally diverse RNA targets. To design new semisynthetic aminoglycosides with improved target selectivity, it is important to understand the energetic and structural basis by which diverse RNA targets recognize similar ligands. It is also imperative to discover how novel aminoglycosides could be rationally designed to have enhanced selectivity for a given target. Two RNA drug targets, the prokaryotic ribosomal A-site and the HIV-1 TAR, provide an excellent model system in which to dissect the issue of target selectivity, in that they each have distinctive interactions with aminoglycosides. We report herein the design, synthesis, and binding activity of novel nucleobase-aminoglycoside conjugates that were engineered to be more selective for the A-site binding pocket. Contrary to the structural design, the conjugates bind the A-site more weakly than does the parent compound and bind the TAR more tightly than the parent compound. This result implies that the two RNA targets differ in their ability to adapt to structurally diverse ligands and thus have inherently different selectivities. This work emphasizes the importance of considering the inherent selectivity traits of the RNA target when engineering new ligands.