title: Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations.
abstract: New pseudo-di- and pseudo-trisaccharide derivatives of the aminoglycoside drug G418 were designed, synthesized and their ability to readthrough nonsense mutations was examined in both in vitro and ex vivo systems, along with the toxicity tests. Two novel lead structures, NB74 and NB84, exhibiting significantly reduced cell toxicity and superior readthrough efficiency than those of gentamicin, were discovered. The superiority 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.
authors.affiliation: The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Igor
authors.initials: I
authors.lastname: Nudelman
authors.forename: Dana
authors.initials: D
authors.lastname: Glikin
authors.forename: Boris
authors.initials: B
authors.lastname: Smolkin
authors.forename: Mariana
authors.initials: M
authors.lastname: Hainrichson
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018389:Codon, Nonsense / Q000187:drug effects*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics; D015195:Drug Design; D030342:Genetic Diseases, Inborn / Q000188:drug therapy* / Q000235:genetics; D005821:Genetic Techniques; D005839:Gentamicins / Q000737:chemistry*; D006801:Humans; D008059:Mucopolysaccharidosis I / Q000188:drug therapy / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics; D014312:Trisaccharides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D052245:Usher Syndromes / Q000188:drug therapy / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D018389:Codon, Nonsense; D005839:Gentamicins; D014312:Trisaccharides; C572445:aminoglycoside NB84; C010680:antibiotic G 418