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A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids.
Nature Chemistry ( IF 19.2 ) Pub Date : 2019-04-22 , DOI: 10.1038/s41557-019-0255-4
Sebastian Arangundy-Franklin 1 , Alexander I Taylor 1 , Benjamin T Porebski 1 , Vito Genna 2 , Sew Peak-Chew 1 , Alexandra Vaisman 3 , Roger Woodgate 3 , Modesto Orozco 2, 4 , Philipp Holliger 1
Affiliation  

The physicochemical properties of nucleic acids are dominated by their highly charged phosphodiester backbone chemistry. This polyelectrolyte structure decouples information content (base sequence) from bulk properties, such as solubility, and has been proposed as a defining trait of all informational polymers. However, this conjecture has not been tested experimentally. Here, we describe the encoded synthesis of a genetic polymer with an uncharged backbone chemistry: alkyl phosphonate nucleic acids (phNAs) in which the canonical, negatively charged phosphodiester is replaced by an uncharged P-alkyl phosphonodiester backbone. Using synthetic chemistry and polymerase engineering, we describe the enzymatic, DNA-templated synthesis of P-methyl and P-ethyl phNAs, and the directed evolution of specific streptavidin-binding phNA aptamer ligands directly from random-sequence mixed P-methyl/P-ethyl phNA repertoires. Our results establish an example of the DNA-templated enzymatic synthesis and evolution of an uncharged genetic polymer and provide a foundational methodology for their exploration as a source of novel functional molecules.

中文翻译:

基于烷基膦酸核酸的具有不带电主链化学的合成遗传聚合物。

核酸的物理化学性质主要由其高度带电的磷酸二酯骨架化学性质决定。这种聚电解质结构将信息内容(碱基序列)与整体特性(如溶解度)分离,并已被提议作为所有信息聚合物的定义特征。然而,这个猜想还没有经过实验验证。在这里,我们描述了具有不带电荷的主链化学的遗传聚合物的编码合成:烷基膦酸核酸 (phNA),其中典型的带负电荷的磷酸二酯被不带电荷的 P-烷基膦酸二酯主链取代。使用合成化学和聚合酶工程,我们描述了 P-甲基和 P-乙基 phNA 的酶促、DNA 模板合成,以及直接从随机序列混合的 P-甲基/P-乙基 phNA 库中定向进化特定的链霉亲和素结合 phNA 适体配体。我们的研究结果建立了一个以 DNA 为模板的酶促合成和不带电遗传聚合物进化的例子,并为它们作为新型功能分子来源的探索提供了基础方法。
更新日期:2019-05-16
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