New derivatives of aminoglycosides containing 6'-carboxylic acid or 6'-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined , 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'-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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071974 | PMC |
| http://dx.doi.org/10.1039/c8md00001h | DOI Listing |
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