About 30 years ago, before the term “chemical biology” was part of our lexicon, a small number of organic chemists recognized that they could apply their skills in synthesis, molecular design and physical characterization to the field of nucleic acid chemistry. Much of this was made easier by Marv Caruther's development of phosphoramidites, which meant that oligonucleotides of DNA and RNA could be made readily and cheaply and that modifications to the bases and sugar–phosphate backbone could be incorporated anywhere in the sequence if the phosphoramidite monomer could be made.^[1] Initially, the phosphoramidite chemistry on an automated synthesizer was (and still is) used in biochemistry and molecular biology to study native nucleic acids and the proteins that manipulate them and to characterize naturally occurring modifications such as methylated, oxidized or isotopically labeled nucleobases.

Then, some creative organic chemists started to go rogue—case in point: Eric Kool. He and others realized that they could imagine and then create completely unnatural bases and base pairs that not only push the boundaries of existing proteins that process DNA and RNA but go fully outside of extant biochemistry. In a landmark paper in 1995, Kool and coworkers describe base pairs with shape complementarity but no hydrogen bonds between the bases.^[2] For example, replacing the oxo groups of thymine with fluorine, making 2,4‐difluorotoluene in a nucleotide (see Figure 1), preserved the ability to make a DNA duplex and led to copying and extension of this nucleotide by native polymerases with high fidelity.^[3] This heralded a new era of innovative biopolymers with designer properties. An alternative approach by his lab showed that one could keep the Watson‐Crick hydrogen bonds but expand the aromatic surface by inserting one or more benzene rings into the base‐paired heterocycles in “xDNA.”^[4] Precise engineering of the sequence of fluorescent aromatic bases in an oligomer led to tunable fluorescence.^[5]

These creative concepts have seen applications in biosensors and chemosensors, and they add to the chemical biology toolbox used to examine, in vitro and in cellulo, the ways that proteins write, read and erase chemical modifications of DNA and RNA.^[6] These applications join other significant outcomes of the Kool research team, ranging from rolling circle amplification of RNA, to methods to monitor and attenuate base excision repair and epigenetics in DNA, to folding properties of RNA.

Eric T. Kool, the George and Hilda Daubert Professor of Chemistry at Stanford University (USA), is the 2019 recipient of the Murray Goodman Memorial Prize, presented by Biopolymers. This special issue of the journal celebrates the award with several contributions on related topics in nucleic acid chemistry, ranging from alternative folding and alternative bases to fluorophores and sensors.

大约 30 年前，在“化学生物学”一词成为我们词汇的一部分之前，少数有机化学家认识到他们可以将合成、分子设计和物理表征方面的技能应用到核酸化学领域。Marv Caruther 对亚磷酰胺的开发使这一切变得更容易，这意味着 DNA 和 RNA 的寡核苷酸可以容易且廉价地制造，并且如果亚磷酰胺单体可以将碱基和糖-磷酸骨架的修饰结合到序列中的任何位置做出来。^{[ 1 ]}最初，自动合成仪上的亚磷酰胺化学被（并且仍然）用于生物化学和分子生物学，以研究天然核酸和操纵它们的蛋白质，并表征自然发生的修饰，例如甲基化、氧化或同位素标记的核碱基。

然后，一些有创造力的有机化学家开始变得无赖——例如：埃里克·库尔（Eric Kool）。他和其他人意识到，他们可以想象并创造出完全非自然的碱基和碱基对，它们不仅突破了现有蛋白质处理 DNA 和 RNA 的界限，而且完全超出了现存的生物化学。在 1995 年的一篇具有里程碑意义的论文中，Kool 及其同事描述了具有形状互补性但碱基之间没有氢键的碱基对。^{[ 2 ]}例如，用氟取代胸腺嘧啶的氧代基团，在核苷酸中生成 2,4-二氟甲苯（见图 1），保留了制造 DNA 双链体的能力，并导致该核苷酸被天然聚合酶复制和延伸具有高保真度。^{[ 3 ]}这预示着具有设计师特性的创新生物聚合物的新时代。他实验室的另一种方法表明，通过将一个或多个苯环插入“xDNA”中碱基配对的杂环中，可以保留 Watson-Crick 氢键，但扩大芳香表面。^{[ 4 ]}寡聚体中荧光芳香碱基序列的精确工程导致可调谐荧光。^{[ 5 ]}

这些创造性的概念已经在生物传感器和化学传感器中得到应用，并且它们添加到用于在体外和细胞中检查蛋白质写入、读取和擦除 DNA 和 RNA 化学修饰的方式的化学生物学工具箱中。^{[ 6 ]}这些应用加入了 Kool 研究团队的其他重要成果，从 RNA 的滚环扩增，到监测和减弱 DNA 中碱基切除修复和表观遗传学的方法，再到 RNA 的折叠特性。

Eric T. Kool 是美国斯坦福大学的 George and Hilda Daubert 化学教授，他是 2019 年由Biopolymers颁发的 Murray Goodman 纪念奖的获得者。该期刊的这期特刊以在核酸化学相关主题上的多项贡献来庆祝该奖项，从替代折叠和替代碱基到荧光团和传感器。