Repairing faulty genes by aminoglycosides: Identification of new pharmacophore with enhanced suppression of disease-causing nonsense mutations

Abstract

New pseudo-trisaccharide derivatives of aminoglycosides containing a chiral methyl group at the side-chain of the ribosamine ring (ring III) were designed, synthesized and their ability to readthrough nonsense mutations was examined in both in vitro and ex vivo systems, along with toxicity tests. Novel lead structures, exhibiting significantly reduced cell toxicity, enhanced specificity to eukaryotic cytoplasmic ribosome, and superior readthrough efficiency compared with those of gentamicin, were discovered. The comparative benefit of new leads was demonstrated in six different nonsense DNA-constructs underling the genetic diseases cystic fibrosis, Duchenne muscular dystrophy, Usher syndrome and Hurler syndrome.