The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery.
The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery.
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DOI：
10.1021/acs.accounts.7b00280
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发表时间：
2017-10-17
影响因子：
18.3
通讯作者：
Wilks TR
中科院分区：
文献类型：
--
作者：
O'Reilly RK;Turberfield AJ;Wilks TR
精确控制反应性和分子结构是化学科学的基本目标。数十亿年的自然选择进化已经产生了能够存储信息，自我复制，催化，捕获和产生光，甚至认知的化学系统。在所有这些情况下，需要控制分子结构以实现特定功能：没有结构控制，功能可能会受损，不可预测或不可能。寻找具有所需功能的分子通常通过合成组合文库来实现，该文库包含一组化学构建块（BB）的许多或所有可能的组合，然后筛选该文库以鉴定“成功”结构。通过常规合成制备的最大文库目前为108个不同分子的数量级。为了说明这一点，有1013种方法可以将21种蛋白质氨基酸排列成长达10个单位的链。鉴于我们知道这些化合物中的一些具有有效的生物活性，因此非常希望能够搜索它们以确定新药分子的线索。可以组合合成大型寡核苷酸库，并使用基于生物复制的系统（例如mRNA展示）将其翻译成肽，并通过DNA测序识别选定的分子;但这些方法仅限于与细胞机制兼容的BB。为了寻找核酸和天然肽以外的广阔化学空间，需要一种替代方法。DNA模板合成（DNA-templated synthesis，简称RT-PCR）可以帮助我们应对这一挑战。通过利用DNA杂交的特异性使选择的反应物紧密接近，并能够在同一反应容器中程序化合成许多不同的产物，从而控制化学产物的形成。通过利用动态的、可编程的DNA过程，有可能设计出一种系统，可以将编码为DNA碱基序列的指令翻译成化学结构--这一过程类似于生物体中核糖体的作用，但有可能创造出化学性质更加多样化的产物。还可以确保每个产物分子用其识别DNA序列标记。以这种方式合成的化合物文库可以暴露于针对合适的靶标的选择，从而富集成功的分子。然后可以使用聚合酶链反应扩增编码DNA，并通过DNA测序解码。更重要的是，DNA指令序列可以在多轮扩增、翻译和选择过程中突变和重复使用。换句话说，它可以作为合成分子进化系统的基础，使我们能够有效地搜索广阔的化学空间。这具有巨大的潜力来彻底改变材料的发现-想象一下能够进化出用于光捕获的分子，或用于二氧化碳固定的催化剂。PCR领域已经发展到可以在DNA模板上进行各种各样的反应的程度。复杂的体系结构和自主的“DNA机器人”已经被实现用于BB的受控组装，并且这些机制反过来使得能够一锅合成大型组合文库。事实上，药物库正在被制药公司利用，并且已经进入药物先导发现计划。这个帐户探讨了参与进化的过程，并强调了在创建一个通用的分子发现系统的挑战。
Precise control over reactivity and molecular structure is a fundamental goal of the chemical sciences. Billions of years of evolution by natural selection have resulted in chemical systems capable of information storage, self-replication, catalysis, capture and production of light, and even cognition. In all these cases, control over molecular structure is required to achieve a particular function: without structural control, function may be impaired, unpredictable, or impossible. The search for molecules with a desired function is often achieved by synthesizing a combinatorial library, which contains many or all possible combinations of a set of chemical building blocks (BBs), and then screening this library to identify “successful” structures. The largest libraries made by conventional synthesis are currently of the order of 108 distinct molecules. To put this in context, there are 1013 ways of arranging the 21 proteinogenic amino acids in chains up to 10 units long. Given that we know that a number of these compounds have potent biological activity, it would be highly desirable to be able to search them all to identify leads for new drug molecules. Large libraries of oligonucleotides can be synthesized combinatorially and translated into peptides using systems based on biological replication such as mRNA display, with selected molecules identified by DNA sequencing; but these methods are limited to BBs that are compatible with cellular machinery. In order to search the vast tracts of chemical space beyond nucleic acids and natural peptides, an alternative approach is required. DNA-templated synthesis (DTS) could enable us to meet this challenge. DTS controls chemical product formation by using the specificity of DNA hybridization to bring selected reactants into close proximity, and is capable of the programmed synthesis of many distinct products in the same reaction vessel. By making use of dynamic, programmable DNA processes, it is possible to engineer a system that can translate instructions coded as a sequence of DNA bases into a chemical structure—a process analogous to the action of the ribosome in living organisms but with the potential to create a much more chemically diverse set of products. It is also possible to ensure that each product molecule is tagged with its identifying DNA sequence. Compound libraries synthesized in this way can be exposed to selection against suitable targets, enriching successful molecules. The encoding DNA can then be amplified using the polymerase chain reaction and decoded by DNA sequencing. More importantly, the DNA instruction sequences can be mutated and reused during multiple rounds of amplification, translation, and selection. In other words, DTS could be used as the foundation for a system of synthetic molecular evolution, which could allow us to efficiently search a vast chemical space. This has huge potential to revolutionize materials discovery—imagine being able to evolve molecules for light harvesting, or catalysts for CO2 fixation. The field of DTS has developed to the point where a wide variety of reactions can be performed on a DNA template. Complex architectures and autonomous “DNA robots” have been implemented for the controlled assembly of BBs, and these mechanisms have in turn enabled the one-pot synthesis of large combinatorial libraries. Indeed, DTS libraries are being exploited by pharmaceutical companies and have already found their way into drug lead discovery programs. This Account explores the processes involved in DTS and highlights the challenges that remain in creating a general system for molecular discovery by evolution.
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影响因子：
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作者：
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影响因子：
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DOI：
10.1073/pnas.89.12.5381
发表时间：
1992-06-15
影响因子：
11.1
作者：
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通讯作者：
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