Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations.
Nonsense mutations promote premature translational termination and represent the underlying cause of a large number of human genetic diseases. The aminoglycoside antibiotic gentamicin has the ability to allow the mammalian ribosome to read past a false-stop signal and generate full-length functional proteins. However, severe toxic side effects along with the reduced suppression efficiency at subtoxic doses limit the use of gentamicin for suppression therapy. We describe here the first systematic development of the novel aminoglycoside 2 (NB54) exhibiting superior in vitro readthrough efficiency to that of gentamicin in seven different DNA fragments derived from mutant genes carrying nonsense mutations representing the genetic diseases Usher syndrome, cystic fibrosis, Duchenne muscular dystrophy, and Hurler syndrome. Comparative acute lethal toxicity in mice, cell toxicity, and the assessment of hair cell toxicity in cochlear explants further indicated that 2 exhibits far lower toxicity than that of gentamicin.
Nudelman
Igor
I
The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Rebibo-Sabbah
Annie
A
Cherniavsky
Marina
M
Belakhov
Valery
V
Hainrichson
Mariana
M
Chen
Fuquan
F
Schacht
Jochen
J
Pilch
Daniel S
DS
Ben-Yosef
Tamar
T
Baasov
Timor
T
D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D001419:Bacteria / Q000187:drug effects; D019556:COS Cells; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense / Q000187:drug effects* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D003593:Cytoplasm / Q000187:drug effects; D004194:Disease / Q000235:genetics*; D055808:Drug Discovery; D016189:Dystrophin / Q000235:genetics; D005839:Gentamicins / Q000494:pharmacology / Q000633:toxicity; D034381:Hearing Loss / Q000139:chemically induced; D006801:Humans; D009843:Oligoribonucleotides / Q000737:chemistry; D010303:Paromomycin / Q000494:pharmacology / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012335:RNA, Ribosomal / Q000737:chemistry; D013696:Temperature
C540944:5-O-(5-amino-5-deoxyribofuranosyl)-1N-(4-amino-2-hydroxybutanoyl)paromamine; D000617:Aminoglycosides; C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D018389:Codon, Nonsense; D016189:Dystrophin; D005839:Gentamicins; D009843:Oligoribonucleotides; D012335:RNA, Ribosomal; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010303:Paromomycin