title: Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy for treatment of genetic diseases caused by nonsense mutations.
abstract: Compelling evidence is now available that gentamicin and Geneticin (G418) can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, toxicity and relative lack of efficacy at subtoxic doses limit the use of gentamicin for suppression therapy. Although G418 exhibits the strongest activity, it is very cytotoxic even at low doses. We describe here the first systematic development of the novel aminoglycoside (S)-11 exhibiting similar in vitro and ex vivo activity to that of G418, while its cell toxicity is significantly lower than those of gentamicin and G418. Using a series of biochemical assays, we provide proof of principle that antibacterial activity and toxicity of aminoglycosides can be dissected from their suppression activity. The data further indicate that the increased specificity toward cytoplasmic ribosome correlates with the increased activity and that the decreased specificity toward mitochondrial ribosome confers the lowered cytotoxicity.
authors.affiliation: The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Jeyakumar
authors.initials: J
authors.lastname: Kandasamy
authors.forename: Dana
authors.initials: D
authors.lastname: Atia-Glikin
authors.forename: Eli
authors.initials: E
authors.lastname: Shulman
authors.forename: Katya
authors.initials: K
authors.lastname: Shapira
authors.forename: Michal
authors.initials: M
authors.lastname: Shavit
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D018389:Codon, Nonsense; D003593:Cytoplasm / Q000187:drug effects*; D030342:Genetic Diseases, Inborn / Q000628:therapy*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000617:Aminoglycosides; D018389:Codon, Nonsense