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Expanding the Scope of Replicable Unnatural DNA: Stepwise Optimization of a Predominantly Hydrophobic Base Pair

机译：扩大可复制的非天然DNA的范围：主要疏水碱基对的逐步优化。

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As part of an ongoing effort to expand the genetic alphabet for in vitro and eventually in vivo applications, we have synthesized a wide variety of predominantly hydrophobic unnatural base pairs exemplified by d>5SICS-d>MMO2 and d>5SICS-d>NaM. When incorporated into DNA, the latter is replicated and transcribed with greater efficiency and fidelity than the former, however previous optimization efforts identified the para and methoxy-distal meta positions of d>MMO2 as particularly promising for further optimization. Here, we report the stepwise optimization of d>MMO2 via the synthesis and evaluation of eighteen novel para-derivatized analogs of d>MMO2, followed by further derivatization and evaluation of the most promising analogs with meta substituents. Subject to size constraints, we find that para substituents can optimize replication via both steric and electronic effects and that meta methoxy groups are unfavorable while fluoro substituents can be beneficial or deleterious depending on the para substituent. In addition, we find that improvements in the efficiency of unnatural triphosphate insertion translate most directly into higher fidelity replication. Importantly, we identify multiple, unique base pair derivatives that when incorporated into DNA are well replicated. The most promising, d>5SICS-d>FEMO, is replicated under some conditions with greater efficiency and fidelity than d>5SICS-d>NaM. These results clearly demonstrate the generality of hydrophobic forces for the control of base pairing within DNA, provide a wealth of new SAR data, and importantly identify multiple new candidates for eventual in vivo evaluation.
机译：作为扩展遗传字母以在体外和最终在体内应用的持续努力的一部分，我们合成了多种主要为疏水性的非天然碱基对，例如d > 5SICS -d > MMO2 < / strong>和d > 5SICS -d > NaM 。当掺入DNA后，后者的复制和转录效率和保真度要比前者更高，但是先前的优化工作发现d > MMO2 的对位和甲氧基-远端间位置对于进一步优化特别有希望。在此，我们报告了d > MMO2 的逐步优化，方法是合成和评估d > MMO2 的18种新型准衍生化类似物，然后进一步衍生化和评估最有前途的具有间位取代基的类似物。受到尺寸限制，我们发现对位取代基可以通过空间和电子效应优化复制，并且间甲氧基是不利的，而氟取代基根据对位取代基可以是有益的或有害的。此外，我们发现非天然三磷酸酯插入效率的提高最直接地转化为更高保真度的复制。重要的是，我们确定了多个独特的碱基对衍生物，这些衍生物在掺入DNA中时可以很好地复制。最有前景的d > 5SICS -d > FEMO 在某些条件下以比d > 5SICS -d > NaM更高的效率和保真度被复制。 。这些结果清楚地证明了疏水力在DNA内控制碱基配对的一般性，提供了大量新的SAR数据，并重要地鉴定了多个新的候选物用于最终的体内评估。

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