Chemical modifications of G418 (geneticin): Synthesis of novel readthrough aminoglycosides results in an improved in vitro safety window but no improvements in vivo.

Ramil Y Baiazitov, Westley Friesen, Briana Johnson, Anna Mollin, Josephine Sheedy, Jairo Sierra, Marla Weetall, Arthur Branstrom, Ellen Welch, Young-Choon Moon

Carbohydrate research 2020 Sep

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G418 is currently the most potent and active aminoglycoside to promote readthrough of eukaryotic nonsense mutations. However, owing to its toxicity G418 cannot be used in vivo to study readthrough activity A robust and scalable method for selective derivatization of G418 was developed to study the biological activity and toxicity of a series of analogs. Despite our synthetic efforts, an improvement in readthrough potency was not achieved. We discovered several analogs that demonstrated reduced zebra fish hair cell toxicity (a surrogate for ototoxicity), but this reduction in cellular toxicity did not translate to reduced in vivo toxicity in rats. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Ramil Y Baiazitov, Westley Friesen, Briana Johnson, Anna Mollin, Josephine Sheedy, Jairo Sierra, Marla Weetall, Arthur Branstrom, Ellen Welch, Young-Choon Moon. Chemical modifications of G418 (geneticin): Synthesis of novel readthrough aminoglycosides results in an improved in vitro safety window but no improvements in vivo. Carbohydrate research. 2020 Sep;495:108058