Chemo-enzymatic Synthesis of Pseudo-trisaccharide Aminoglycoside Antibiotics with Enhanced Nonsense Read-through Inducer Activity
DC Field | Value | Language |
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dc.contributor.author | Lee, Na Joon | - |
dc.contributor.author | Kang, Woongshin | - |
dc.contributor.author | Kwon, Younghae | - |
dc.contributor.author | Oh, Jae Wook | - |
dc.contributor.author | Jung, Hogwuan | - |
dc.contributor.author | Seo, Minsuk | - |
dc.contributor.author | Seol, Yurin | - |
dc.contributor.author | Wi, Jae Bok | - |
dc.contributor.author | Ban, Yeon Hee | - |
dc.contributor.author | Yoon, Yeo Joon | - |
dc.contributor.author | Park, Je Won | - |
dc.date.accessioned | 2022-12-11T20:40:43Z | - |
dc.date.available | 2022-12-11T20:40:43Z | - |
dc.date.created | 2022-12-08 | - |
dc.date.issued | 2022 | - |
dc.identifier.issn | 1860-7179 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/147083 | - |
dc.description.abstract | Aminoglycosides (AGs) are broad-spectrum antibiotics used to treat bacterial infections. 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-length 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-trisaccharide analogs were synthesized by chemo-enzymatic synthesis by acid hydrolysis of commercially available AGs, followed by an enzymatic reaction using recombinant substrate-flexible 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-N-acylation, 3 ',4 '-dideoxygenation, and post-glycosyl transfer modifications on the third sugar moiety of AGs diminishes their antibacterial activities. The 3 ',4 '-dihydroxy and 6 '-hydroxy moieties regulate the in vitro nephrotoxicity of AGs in mammalian cell lines. The 3 ',4 '-dihydroxy and 6 '-methyl scaffolds are indispensable for the ex vivo NRI activity of AGs. Based on the alleviated in vitro antibacterial properties and nephrotoxicity, and the highest ex vivo NRI activity among the five compounds, a kanamycin analog (6 '-methyl-3 ''-deamino-3 ''-hydroxykanamycin C) was selected as a novel AG hit for further studies on human genetic disorders caused by premature transcriptional termination. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | WILEY-V C H VERLAG GMBH | - |
dc.subject | CYSTIC-FIBROSIS | - |
dc.subject | GENETIC-DISEASE | - |
dc.subject | STOP MUTATIONS | - |
dc.subject | CFTR FUNCTION | - |
dc.subject | SUPPRESSION | - |
dc.subject | THERAPY | - |
dc.subject | EXPRESSION | - |
dc.subject | PATHWAYS | - |
dc.subject | CODONS | - |
dc.subject | RNA | - |
dc.title | Chemo-enzymatic Synthesis of Pseudo-trisaccharide Aminoglycoside Antibiotics with Enhanced Nonsense Read-through Inducer Activity | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Park, Je Won | - |
dc.identifier.doi | 10.1002/cmdc.202200497 | - |
dc.identifier.scopusid | 2-s2.0-85141636307 | - |
dc.identifier.wosid | 000879913300001 | - |
dc.identifier.bibliographicCitation | CHEMMEDCHEM | - |
dc.relation.isPartOf | CHEMMEDCHEM | - |
dc.citation.title | CHEMMEDCHEM | - |
dc.type.rims | ART | - |
dc.type.docType | Article; Early Access | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Medicinal | - |
dc.relation.journalWebOfScienceCategory | Pharmacology & Pharmacy | - |
dc.subject.keywordPlus | CYSTIC-FIBROSIS | - |
dc.subject.keywordPlus | GENETIC-DISEASE | - |
dc.subject.keywordPlus | STOP MUTATIONS | - |
dc.subject.keywordPlus | CFTR FUNCTION | - |
dc.subject.keywordPlus | SUPPRESSION | - |
dc.subject.keywordPlus | THERAPY | - |
dc.subject.keywordPlus | EXPRESSION | - |
dc.subject.keywordPlus | PATHWAYS | - |
dc.subject.keywordPlus | CODONS | - |
dc.subject.keywordPlus | RNA | - |
dc.subject.keywordAuthor | aminoglycosides | - |
dc.subject.keywordAuthor | KanM2 | - |
dc.subject.keywordAuthor | 6 &apos | - |
dc.subject.keywordAuthor | -methyl-3 &apos | - |
dc.subject.keywordAuthor | &apos | - |
dc.subject.keywordAuthor | -deamino-3 &apos | - |
dc.subject.keywordAuthor | &apos | - |
dc.subject.keywordAuthor | -hydroxykanamycin C | - |
dc.subject.keywordAuthor | nonsense readthrough inducer activity | - |
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