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Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 May 14; Vol. 52 (9), pp. 2836-45. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Aminoglycosides chemical synthesis
Aminoglycosides chemistry
Animals
Bacteria drug effects
COS Cells
Cadherin Related Proteins
Cadherins genetics
Cell Survival drug effects
Chlorocebus aethiops
Codon, Nonsense genetics
Cystic Fibrosis Transmembrane Conductance Regulator genetics
Cytoplasm drug effects
Dystrophin genetics
Gentamicins pharmacology
Gentamicins toxicity
Hearing Loss chemically induced
Humans
Oligoribonucleotides chemistry
Paromomycin pharmacology
Paromomycin toxicity
Protein Biosynthesis drug effects
RNA Stability drug effects
RNA, Ribosomal chemistry
Temperature
Aminoglycosides pharmacology
Aminoglycosides toxicity
Codon, Nonsense drug effects
Disease genetics
Drug Discovery
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19309154
- Full Text :
- https://doi.org/10.1021/jm801640k