Aminoglycosides and uses thereof in the treatment of genetic disorders
View Patent ↗A new class of paromomycin-derived aminoglycosides, which exhibit efficient stop-codon mutation suppression activity, low toxicity and high selectivity towards eukaryotic cells are provided. Also provided are chemical and chemo-enzymatic processes of preparing these paromomycin-derived aminoglycosides and intermediates thereof, as well as pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders.
1. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety, at least one of R 1 , R 2 and R 3 being a monosaccharide moiety having the general Formula II:
wherein each of R 6 , R 7 and R 8 is independently selected from the group consisting of hydroxyl and amine, or R 1 being an oligosaccharide moiety,
whereas when R 2 is said monosaccharide moiety having said Formula II, R 6 is amine;
X is oxygen or sulfur;
R 4 is (S)-4-amino-2-hydroxybutyryl (AHB);
R 5 is hydroxyl;
Y is hydrogen or alkyl; and
each of the dashed lines indicates independently an R configuration or an S configuration.
2. The method of claim 1 , wherein said compound is:
3. The method of claim 1 , wherein X is oxygen.
4. The method of claim 1 , wherein Y is hydrogen.
5. The method of claim 1 , wherein at least one of R 1 , R 2 and R 3 is a disaccharide moiety.
6. The method of claim 1 , wherein Y is alkyl.
7. The method of claim 1 , wherein said premature stop codon mutation is associated with a genetic disorder, the method being for treating said genetic disorder in the subject.
8. The method of claim 7 , wherein said genetic disorder is selected from the group consisting of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome, Tay-Sachs Becker muscular dystrophy (BMD), Congenital muscular dystrophy (CMD), Factor VII deficiency, Familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, Mucopolysaccharidosis, Nephropathic cystinosis, Polycystic kidney disease, Rett syndrome, Spinal muscular atrophy (SMA), X-linked nephrogenic diabetes insipidus (XNDI) and X-linked retinitis pigmentosa.
9. A method inducing readthrough of a premature stop codon mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, hydroxyl, amine or an oligosaccharide moiety, and at least one of R 1 , R 2 and R 3 being a monosaccharide moiety having the general Formula II:
wherein each of R 6 , R 7 and R 8 is independently selected from the group consisting of hydroxyl and amine, or R 1 being an oligosaccharide;
X is oxygen or sulfur;
R 4 is hydrogen;
R 5 is hydroxyl;
Y is hydrogen; and
each of the dashed line indicates independently an R configuration or an S configuration,
with the proviso that said compound is not selected from the group consisting of
and paromomycin.
10. The method of claim 9 , wherein X is oxygen.
11. The method of claim 9 , wherein said compound is:
12. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety,
X is oxygen or sulfur;
R 4 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB);
R 5 is hydroxyl or amine;
Y is alkyl; and
each of the dashed line indicates independently an R configuration or an S configuration,
and wherein:
at least one of R 1 , R 2 and R 3 is selected from a monosaccharide moiety and an oligosaccharide moiety; and/or
R 4 is (S)-4-amino-2-hydroxybutyryl (AHB),
with the proviso that said compound is not G-418.
13. The method of claim 12 , wherein X is oxygen.
14. The method of claim 12 , wherein R 5 is hydroxyl.
15. The method of claim 12 , wherein at least one of R 1 , R 2 and R 3 is a monosaccharide moiety.
16. The method of claim 15 , wherein R 4 is AHB.
17. The method of claim 12 , wherein said compound is:
18. The method of claim 12 , wherein said premature stop codon mutation is associated with a genetic disorder, the method being for treating said genetic disorder in the subject.
19. The method of claim 18 , wherein said genetic disorder is selected from the group consisting of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome, Tay-Sachs Becker muscular dystrophy (BMD), Congenital muscular dystrophy (CMD), Factor VII deficiency, Familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, Mucopolysaccharidosis, Nephropathic cystinosis, Polycystic kidney disease, Rett syndrome, Spinal muscular atrophy (SMA), X-linked nephrogenic diabetes insipidus (XNDI) and X-linked retinitis pigmentosa.
20. A method of inducing readthrough of a premature stop codon mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each of R 1 , R 2 and R 3 is independently a monosaccharide moiety, halide, hydroxyl, amine or an oligosaccharide moiety,
X is oxygen or sulfur;
R 4 is (S)-4-amino-2-hydroxybutyryl (AHB);
R 5 is hydroxyl or amine;
Y is alkyl; and
each of the dashed line indicates independently an R configuration or an S configuration.
21. The method of claim 20 , wherein X is oxygen.
22. The method of claim 20 , wherein R 5 is hydroxyl.
23. The method of claim 20 , wherein at least one of R 1 , R 2 and R 3 is a monosaccharide moiety.
24. The method of claim 20 , wherein said premature stop codon mutation is associated with a genetic disorder, the method being for treating said genetic disorder in the subject.
25. The method of claim 24 , wherein said genetic disorder is selected from the group consisting of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome, Tay-Sachs Becker muscular dystrophy (BMD), Congenital muscular dystrophy (CMD), Factor VII deficiency, Familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, Mucopolysaccharidosis, Nephropathic cystinosis, Polycystic kidney disease, Rett syndrome, Spinal muscular atrophy (SMA), X-linked nephrogenic diabetes insipidus (XNDI) and X-linked retinitis pigmentosa.