Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

  • Bioorg Med Chem. 2010 Jun 1;18(11):3735-46. doi: 10.1016/j.bmc.2010.03.060.
Igor Nudelman  1 ,  Dana Glikin ,  Boris Smolkin ,  Mariana Hainrichson ,  Valery Belakhov ,  Timor Baasov
Affiliations
  • 1. The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Technion-Israel Institute of Technology, Haifa 32000, Israel.
PMID: 20409719 DOI: 10.1016/j.bmc.2010.03.060
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.