碱基的化学修饰与功能核酸研究

Chemical modifications of nucleobases in functional nucleic acids

核酸的多样化功能正在逐渐被揭示出来,从核酶的催化功能,适配体特异性结合靶分子,到小RNA分子对于基因的干扰和调控,4种碱基和核糖-磷酸单元骨架借助多样化的高级结构展现出的化学活性和生物活性远非我们现在的认识水平,或许还有更多的功能等待开发出来。从这些天然和非天然功能核酸的结构和机制研究中,碱基替换和消除作为最常用的研究方法,使我们认识到碱基以平面堆积、静电作用、络合作用、氢键,尤其是广义酸碱的方式参与功能结构域的形成和化学反应。自然选择和人工筛选的功能核酸都具有高度的序列保守性,但从10-23脱氧核酶的功能基修饰获得了能提高催化反应速率的修饰位点和先导结构。因此,基于功能基水平的化学修饰,让我们看到了优化功能核酸的可能性,为更好地发挥功能核酸在研究工具和治疗药物方面的潜力带来了希望,虽然对于每一种功能核酸的优化修饰,引入何种功能基和如何引入功能基都是一种挑战。

The diversity of functional nucleic acids is being explored from nature and in vitro selections,including ribozyme catalysis,aptamer binding to target molecules with high specific and affinity,and RNA interference and modulation of gene expression. The great potential of chemical and biological activity of four nucleobases and the sugar-phosphate backbone in various specific tertiary structures is beyond our present imagination,and more functions remain to be found. Therefore,developing insight into the structural basis of these functional nucleic acids is invaluable in understanding their mechanisms and exploring the applications. With a special focus on the four nucleobases,we learnt that nucleobases could contribute to the functions by base stacking,electrostatic interactions,complexion with metal ions,hydrogen bonding,and even act as general acid-base in specific functions. Deletion and substitution of each nucleobases demonstrated the conservation of all the natural and unnatural functional nucleic acids. But from the success of chemical modifications at the level of functional groups on 10-23 DNAzyme,there is still room for the optimization of functional nucleic acids,for practical applications as research tools and genetic therapeutics. It is a big challenge for any functional nucleic acids,to conduct the chemical modification in a right way in the complex tertiary structures,including which residue could be used for chemical modification and which functional groups could be introduced for an expected positive effect.