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Over the last two decades, studies have reported the potential of AGs in the treatment of genetic disorders caused by nonsense mutations, owing to their ability to induce the ribosomes to read through these mutations and produce a full\u2010length protein. However, the principal limitation in the clinical application of AGs arises from their high toxicity, including nephrotoxicity and ototoxicity. In this study, five novel pseudo\u2010trisaccharide analogs were synthesized by chemo\u2010enzymatic synthesis by acid hydrolysis of commercially available AGs, followed by an enzymatic reaction using recombinant substrate\u2010flexible KanM2 glycosyltransferase. The relationships between their structures and biological activities, including the antibacterial, nephrotoxic, and nonsense readthrough inducer (NRI) activities, were investigated. The absence of 1\u2010N\u2010acylation, 3\u2032,4\u2032\u2010dideoxygenation, and post\u2010glycosyl transfer modifications on the third sugar moiety of AGs diminishes their antibacterial activities. The 3\u2032,4\u2032\u2010dihydroxy and 6\u2032\u2010hydroxy moieties regulate the in\u2005vitro nephrotoxicity of AGs in mammalian cell lines. The 3\u2032,4\u2032\u2010dihydroxy and 6\u2032\u2010methyl scaffolds are indispensable for the <jats:italic>ex vivo<\/jats:italic> NRI activity of AGs. Based on the alleviated <jats:italic>in\u2005vitro<\/jats:italic> antibacterial properties and nephrotoxicity, and the highest <jats:italic>ex vivo<\/jats:italic> NRI activity among the five compounds, a kanamycin analog (6\u2032\u2010methyl\u20103\u2032\u2032\u2010deamino\u20103\u2032\u2032\u2010hydroxykanamycin C) was selected as a novel AG hit for further studies on human genetic disorders caused by premature transcriptional termination.<\/jats:p>","DOI":"10.1002\/cmdc.202200497","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T04:49:00Z","timestamp":1666154940000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chemo\u2010enzymatic Synthesis of Pseudo\u2010trisaccharide Aminoglycoside Antibiotics with Enhanced Nonsense Read\u2010through Inducer Activity"],"prefix":"10.1002","volume":"18","author":[{"given":"Na 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