The Pattern of Distribution of Amino Groups Modulates the Structure and Dynamics of Natural Aminoglycosides: Implications for RNA Recognition

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• 作者：Francisco Corzana ; Igor Cuesta ; Felix Freire ; Julia Revuelta ; Mario Torrado ; Agatha Bastida ; Jesú ; s Jimé ; nez-Barbero ; Juan Luis Asensio
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：March 14, 2007
• 年：2007
• 卷：129
• 期：10
• 页码：2849 - 2865
• 全文大小：1266K
• 年卷期：v.129,no.10(March 14, 2007)
• ISSN：1520-5126

文摘

Aminoglycosides are clinically relevant antibiotics that participate in a large variety of molecularrecognition processes involving different RNA and protein receptors. The 3-D structures of these policationicoligosaccharides play a key role in RNA binding and therefore determine their biological activity. Herein,we show that the particular NH₂/NH₃⁺/OH distribution within the antibiotic scaffold modulates theoligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkageshave a significant influence on the antibiotic structure. A careful NMR/theoretical analysis of different naturalaminoglycosides, their fragments, and synthetic derivatives proves that both hydrogen bonding and charge-charge repulsive interactions are at the origin of this effect. Current strategies to obtain new aminoglycosidederivatives are mainly focused on the optimization of the direct ligand/receptor contacts. Our results stronglysuggest that the particular location of the NH₂/NH₃⁺/OH groups within the antibiotics can also modulatetheir RNA binding properties by affecting the conformational preferences and inherent flexibility of thesedrugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.