Balancing Nonsense Mutation Readthrough and Toxicity of Designer Aminoglycosides for Treatment of Genetic Diseases

New derivatives of aminoglycosides with a side chain 1,2-aminoalcohol at the 5 position of ring III were designed, synthesized, and biologically evaluated. The novel lead structure (compound 6), exhibiting substantially enhanced selectivity toward eukaryotic versus prokaryotic ribosome, high readthrough activity, and considerably lower toxicity than the previous lead compounds, was discovered. Balanced readthrough activity and toxicity of 6 were demonstrated in three different nonsense DNA-constructs underlying the genetic diseases, cystic fibrosis and Usher syndrome, and in two different cell lines, baby hamster kidney and human embryonic kidney cells. Molecular dynamics simulations within the A site of the 80S yeast ribosome demonstrated a remarkable kinetic stability of 6, which potentially determines its high readthrough activity.

Automated summary

New derivatives of aminoglycosides with a 1,2-aminoalcohol side chain at the 5 position of ring III were synthesized and evaluated. Compound 6, a novel lead structure, showed enhanced selectivity towards eukaryotic ribosomes, high readthrough activity, and lower toxicity compared to previous compounds. Molecular dynamics simulations revealed the kinetic stability of compound 6 within the A site of the 80S yeast ribosome, which potentially contributes to its high readthrough activity.