Discovery of Aminoglycoside Mimetics by NMR-Based Screening of Escherichia coli A-site RNA

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• 作者：Liping Yu ; Thorsten K. Oost ; Jeffrey M. Schkeryantz ; Jianguo Yang ; Dave Janowick ; and Stephen W. Fesik
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：April 16, 2003
• 年：2003
• 卷：125
• 期：15
• 页码：4444 - 4450
• 全文大小：255K
• 年卷期：v.125,no.15(April 16, 2003)
• ISSN：1520-5126

文摘

A method is described for the NMR-based screening for the discovery of aminoglycoside mimeticsthat bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit highnephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to importantmicrobial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcomethe problems associated with toxicities and resistance development observed with the aminoglycosides,we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening ofour compound library in search for small-molecule RNA binders against this RNA target. From these studies,several classes of compounds were identified as initial hits with binding affinities in the range of 70 M to3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of severalsmall-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides.Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensionalstructures of the RNA/aminoglycoside complexes.