The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential

作者：Westley J. Friesen, Briana Johnson, Jairo Sierra, Jin Zhuo, Priya Vazirani, Xiaojiao Xue, Yuki Tomizawa, Ramil Baiazitov, Christie Morrill, Hongyu Ren, Suresh Babu, Young‐Choon Moon, Art Branstrom, Anna Mollin, Jean Hedrick, Josephine Sheedy, Gary Elfring, Marla Weetall, Joseph M. Colacino, Ellen Welch, Stuart W. Peltz · 发表于：PLoS ONE · 年份：2018 · DOI：10.1371/journal.pone.0206158 · 被引用次数：39 · 研究领域：RNA and protein synthesis mechanisms、Advanced biosensing and bioanalysis techniques、Viral Infections and Immunology Research

Nonsense mutations, resulting in a premature stop codon in the open reading frame of mRNAs are responsible for thousands of inherited diseases. Readthrough of premature stop codons by small molecule drugs has emerged as a promising therapeutic approach to treat disorders resulting from premature termination of translation. The aminoglycoside antibiotics are a class of molecule known to promote readthrough at premature termination codons. Gentamicin consists of a mixture of major and minor aminoglycoside components. Here, we investigated the readthrough activities of the individual components and show that each of the four major gentamicin complex components representing 92-99% of the complex each had similar potency and activity to that of the complex itself. In contrast, a minor component (gentamicin X2) was found to be the most potent and active readthrough component in the gentamicin complex. The known oto- and nephrotoxicity associated with aminoglycosides preclude long-term use as readthrough agents. Thus, we evaluated the components of the gentamicin complex as well as the so-called "designer" aminoglycoside, NB124, for in vitro and in vivo safety. In cells, we observed that gentamicin X2 had a safety/readthrough ratio (cytotoxicity/readthrough potency) superior to that of gentamicin, G418 or NB124. In rodents, we observed that gentamicin X2 showed a safety profile that was superior to G418 overall including reduced nephrotoxicity. These results support further investig...