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David S. Grierson - One of the best experts on this subject based on the ideXlab platform.

  • 2 aminothiazole 4 carboxamides enhance readthrough of premature termination codons by aminoglycosides
    ACS Medicinal Chemistry Letters, 2019
    Co-Authors: Safwat M. Rabea, Aruna D. Balgi, Alexandra Krause, Sara Hosseini Farahabadi, Michel Roberge, Alireza Baradaranheravi, David S. Grierson
    Abstract:

    Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR.

  • 2‑Aminothiazole-4-carboxamides Enhance Readthrough of Premature Termination Codons by Aminoglycosides
    2019
    Co-Authors: Safwat M. Rabea, Alireza Baradaran-heravi, Aruna D. Balgi, Alexandra Krause, Sara Hosseini Farahabadi, Michel Roberge, David S. Grierson
    Abstract:

    Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR

Tatiyana V Serebryanskaya - One of the best experts on this subject based on the ideXlab platform.

Safwat M. Rabea - One of the best experts on this subject based on the ideXlab platform.

  • 2 aminothiazole 4 carboxamides enhance readthrough of premature termination codons by aminoglycosides
    ACS Medicinal Chemistry Letters, 2019
    Co-Authors: Safwat M. Rabea, Aruna D. Balgi, Alexandra Krause, Sara Hosseini Farahabadi, Michel Roberge, Alireza Baradaranheravi, David S. Grierson
    Abstract:

    Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR.

  • 2‑Aminothiazole-4-carboxamides Enhance Readthrough of Premature Termination Codons by Aminoglycosides
    2019
    Co-Authors: Safwat M. Rabea, Alireza Baradaran-heravi, Aruna D. Balgi, Alexandra Krause, Sara Hosseini Farahabadi, Michel Roberge, David S. Grierson
    Abstract:

    Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR

Hidenori Hayashi - One of the best experts on this subject based on the ideXlab platform.

  • peroxisomal cholesterol synthesis in vivo accumulation of 4 methyl intermediate sterols after Aminotriazole inhibition of cholesterol synthesis
    Biochimica et Biophysica Acta, 1994
    Co-Authors: Fumie Hashimoto, Hidenori Hayashi
    Abstract:

    Abstract To clarify the importance and pathway of peroxisomal cholesterol synthesis in vivo, we have examined whether or not 4,4-dimethyl-5α-cholest-8-en-3β-ol and 4α-methyl-5α-cholest-7-en-3β-olare accumulated in hepatic peroxisomes of aminotriα-zole-treated rats (we have shown that these intermediate steroids accumulate in rat liver when cholesterol synthesis is inhibited by Aminotriazole: Hashimoto, F. and Hayashi, H. (1991) Biochim. Biophys. Acta 1086, 115). Differential centrifugation and Nycodenz gradient centrifugation showed that these intermediate steroids were localized in peroxisomes and microsomes. Cholestyramine (3-hydroxy-3-methylglutaryl-CoA reductase activator) pretreatment of Aminotriazole-treated rats increased the contents of the intermediate steroids in both peroxisomes and microsomes. In peroxisomes, both 4α-methyl-5α-cholest-7-en-3β-ol and 4,4-dimethyl-5α-cholest-8-en-3β-ol were increased to about 3 times the control (Aminotriazole-treated rat), and they were predominantly (about 70%) recovered in the membrane fraction after treatment with 0.05% deoxycholate or 100 mM Na 2 CO 3 . Gemfibrozil (peroxisomal proliferator) pretreatment enhanced the contents of 4α-methyl-5α-cholest-7-en-3β-ol and 4,4-di-methyl-5α-cholest-8-en- of peroxisomes to 4.5 times and 37 times the control, respectively. The effects of Aminotriazole, cholestyramine and gemfibrozil on the intermediate contents were different between peroxisomes and microsomes. We suggest that peroxisomes in addition to microsomes participate in cholesterol synthesis in vivo, and the biosynthetic pathway includes 4α-methyl-5α-cholest-7-en-3β-ol and 4,4-dimethyl-5α-cholest-8-en-3β-ol.

  • effects of Aminotriazole treatment on biosyntheses of primary bile acids in vivo
    Chemical & Pharmaceutical Bulletin, 1992
    Co-Authors: Fumie Hashimoto, Chishio Sugimoto, Hidenori Hayashi
    Abstract:

    The influence of aminotriaxole treatment on primary bile acid biosynthesis was studied in detail. After administration of Aminotriazole to rats, bile was collected for 8h. The content of chenodeoxycholic acid in the bile was increased to 144% of the control by Aminotriazole treatment, but that of cholic acid was decreased to 48.4%. In another experiment, [4-14C]cholesterol was injected into rats immediately after Aminotriazole treatment. and then bile was collected. The content of radioactive chenodeoxycholic acid in the bile was significantly increased to 130% of the control, but that of ratioactive cholic acid was unchanged. In a similar experiment with [2-14C]mevalonate, the content of radioactive chenodeoxycholic acid in the bile was hardly changed by Aminotriazole treatment, but that of radioactive cholic acid was greatly decreased to 41.2% of the control. Aminotriazole treatment did not affect the ratios of tauroconjugate to glycoconjugate of the two bile acids.Thus, Aminotriazole treatment affects the syntheses of not only cholesterol (F. Hashimoto, C. Sugimoto and H. Hayashi, Chem. Pharm. Bull., 38, 2532 (1990); F. Hashimoto and H. Hayashi, Biochim. Biophys. Acta, 1086, 115 (1991) but also primary bile acids in vivo. Namely, Aminotriazole treatment activated biosynthesis of chenodeoxycholic acid from exogenous cholesterol, but did not affect that of cholic acid. Aminotriazole hardly affected the synthesis of chenodeoxycholic acid through endogenous cholesterol (from mevalonate), but inhibited that of cholic acid.

  • identification of intermediates after inhibition of cholesterol synthesis by Aminotriazole treatment in vivo
    Biochimica et Biophysica Acta, 1991
    Co-Authors: Fumie Hashimoto, Hidenori Hayashi
    Abstract:

    Cholesterol synthesis from mevalonate is inhibited by Aminotriazole treatment in vivo. We tried to identify intermediates accumulated in liver of Aminotriazole-treated rats. At 6 h after the Aminotriazole treatment, the liver was excised. Sterols were extracted from it, and subjected to capillary gas-liquid chromatography, high-performance liquid chromatography, gas-liquid chromatography linked to mass spectrometry and gas-liquid chromatography linked to Fourier-transform infrared spectrometry. It was found that 4α-methyl-5α-cholest-7-en-3s-ol and 4,4-dimethyl-5α-cholest-8-en-3s-ol were accumulated in the liver, mainly as the free forms. The contents of the former and the latter were increased to 25- and 64-times the control values, respectively. In another experiment, [2-13C]mevalonate was injected at 2 h after Aminotriazole treatment, and 4 h later the liver was excised. The sterols extracted from the liver were subjected to gas-liquid chromatography linked to mass spectrometry. Specific fragment ions reflecting the incorporation of [13C] mevalonate were detected in the mass spectra of the intermediate sterols. Accumulation of 4α-methyl-5α-cholest-7-en-3s-ol and 4,4-dimethyl-5α-cholest-8-en-3s-ol after Aminotriazole treatment suggests that elimination of the 4α-methyl group from 4-methyl intermediate sterols is inhibited by Aminotriazole.

Ingo Ott - One of the best experts on this subject based on the ideXlab platform.