Exploring eukaryotic versus prokaryotic ribosomal RNA recognition with aminoglycoside derivatives

New derivatives of aminoglycosides containing 6[prime or minute]-carboxylic acid or 6[prime or minute]-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined in vitro, along with the protein translation inhibition in prokaryotic and eukaryotic systems. The observed structure-activity relationships, along with the comparative molecular dynamics simulations within the eukaryotic rRNA decoding site, showed high sensitivity of 6[prime or minute]-position to substitution, indicating that the rational design of potent stop-codon read-through inducers requires consideration of not only the structure and energetics of the drug-RNA interaction but also the dynamics associated with that interaction.