Corzana Francisco, Cuesta Igor, Freire Felix, Revuelta Julia, Torrado Mario, Bastida Agatha, Jiménez-Barbero Jesús, Asensio Juan Luis
Contribution from the Instituto de Química OrgAnica General and Centro de Investigaciones Biológicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
J Am Chem Soc. 2007 Mar 14;129(10):2849-65. doi: 10.1021/ja066348x. Epub 2007 Feb 14.
Aminoglycosides are clinically relevant antibiotics that participate in a large variety of molecular recognition processes involving different RNA and protein receptors. The 3-D structures of these policationic oligosaccharides 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 the oligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkages have a significant influence on the antibiotic structure. A careful NMR/theoretical analysis of different natural aminoglycosides, 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 aminoglycoside derivatives are mainly focused on the optimization of the direct ligand/receptor contacts. Our results strongly suggest that the particular location of the NH2/NH3(+)/OH groups within the antibiotics can also modulate their RNA binding properties by affecting the conformational preferences and inherent flexibility of these drugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.
氨基糖苷类是具有临床相关性的抗生素，参与涉及不同RNA和蛋白质受体的多种分子识别过程。这些聚阳离子寡糖的三维结构在RNA结合中起关键作用，因此决定了它们的生物活性。在此，我们表明抗生素支架内特定的NH2/NH3(+)/OH分布调节寡糖的构象和灵活性。特别是，糖苷键两侧的那些极性基团对抗生素结构有重大影响。对不同天然氨基糖苷类、其片段和合成衍生物进行仔细的核磁共振/理论分析证明，氢键和电荷-电荷排斥相互作用都是这种效应的根源。目前获得新氨基糖苷类衍生物的策略主要集中在优化直接的配体/受体接触。我们的结果强烈表明，抗生素内NH2/NH3(+)/OH基团的特定位置也可以通过影响这些药物的构象偏好和固有灵活性来调节它们的RNA结合特性。在设计具有更高活性的新抗生素时，这一事实也应予以仔细考虑。
