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Found 1 result for PubMed Citation for id: 1948687
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. 2023 Apr 27;14(6):794-801.
doi: 10.1021/acsmedchemlett.3c00089. eCollection 2023 Jun 8.

Balancing Nonsense Mutation Readthrough and Toxicity of Designer Aminoglycosides for Treatment of Genetic Diseases

Sandip Guchhait  1 , Alina Khononov  1 , Tomasz Pieńko  1 , Valery Belakhov  1 , Timor Baasov  1
Affiliations

Balancing Nonsense Mutation Readthrough and Toxicity of Designer Aminoglycosides for Treatment of Genetic Diseases

Sandip Guchhait et al. ACS Med Chem Lett. .

Abstract

New derivatives of aminoglycosides with a side chain 1,2-aminoalcohol at the 5" position of ring III were designed, synthesized, and biologically evaluated. The novel lead structure (compound 6), exhibiting substantially enhanced selectivity toward eukaryotic versus prokaryotic ribosome, high readthrough activity, and considerably lower toxicity than the previous lead compounds, was discovered. Balanced readthrough activity and toxicity of 6 were demonstrated in three different nonsense DNA-constructs underlying the genetic diseases, cystic fibrosis and Usher syndrome, and in two different cell lines, baby hamster kidney and human embryonic kidney cells. Molecular dynamics simulations within the A site of the 80S yeast ribosome demonstrated a remarkable kinetic stability of 6, which potentially determines its high readthrough activity.

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Conflict of interest statement

The authors declare the following competing financial interest(s): T.B. declares that the compounds 1-7 discussed in this publication are subject to license agreement granted to a commercial third party.

Figures

Figure 1
Figure 1
Chemical structures of synthetic AGs that were investigated in this study.
Scheme 1
Scheme 1
Reagents and conditions: (i) (a) TBSCl, Py, 0–25 °C, 92%, (b) BzCl, Py, DMAP, 0–25 °C, 88%; (ii) (a) TBAF, 0–25 °C, 7 h, 79%; (b) TsCl, Py, DMAP, 0–25 °C, 74%; (iii) (a) NBS, Acetone:H2O [9:1], −30 °C; (b) CCl3CN, DBU, CH2Cl2, 0 °C, 94% over 2 steps.
Scheme 2
Scheme 2
Reagents and conditions: (i) (a) BF3·Et2O, dry CH2Cl2, −30 °C; (b) MeNH2 (33% in EtOH), 25 °C, 68% after 2 steps; (ii) (a) HOCH2CH2NH2, MeOH/H2O(1:1), 80 °C, 86%; (b) PMe3, NaOH (0.1 M), THF, 25 °C, 53%; (iii) (a) (S)-3-aminopropane-1,2-diol, MeOH/H2O(1:1), 80 °C, 71%; (b) PMe3, NaOH (0.1 M), THF, 25 °C, 53%; (iv) (a) (R)-3-aminopropane-1,2-diol, MeOH/H2O(1:1), 80 °C, 76%; (b) PMe3, NaOH (0.1 M), THF, 25 °C, 64%.
Scheme 3
Scheme 3
Reagents and conditions: (i) DEAD, PPh3, phthalimide, THF, 0-25 °C, 86%; (ii) (a) CSA, MeOH/CH2Cl2 (1:1), 40 °C, 90%; (b) Py, BzCl, DMAP, 0-25 °C, 98%; (iii) (a) NBS, Acetone/H2O(9:1), −30 °C; (b) CCl3CN, DBU, CH2Cl2, 0 °C, 94% after 2 steps.
Scheme 4
Scheme 4
Reagents and conditions. (i) BF3·Et2O, dry CH2Cl2, −30 °C, 89%; (ii) MeNH2 (33% in EtOH), 25 °C, 83%; (iii) (a) Cs2CO3, HOCH2CH2Br, CH3CN, 70 °C, (b) PMe3, NaOH (0.1 M), THF, 0-25 °C, 27% of 6 after 2 steps, 37% of 7 after 2 steps.
Figure 2
Figure 2
Comparative in vitro stop codon suppression levels induced by compounds 1–7 in R3X construct, representing Usher-1 syndrome. The assays were performed as previously described by us. The results are averages of at least three independent experiments.
Figure 3
Figure 3
Comparative in vitro stop codon suppression level induced by compounds 1, 2, 3, and 6 in two different nonsense constructs, G542X and W1282X, representing cystic fibrosis. The assays were performed as previously described by us. The results are averages of at least three independent experiments.
Figure 4
Figure 4
Binding modes of compounds 1, 2, 3, and 6 in the A site of eukaryotic ribosome. For clarity, only the interactions involving ring III (in dark green and highlighted with yellow background) are shown. rRNA nucleotides are numbered according to the E. coli numbering. Hydrogen bonds and salt bridges are presented as black dashed lines and bond lengths are in Å.
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