Synthesis at the Interface of Chemistry and Biology,Accounts of Chemical Research

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Synthesis at the Interface of Chemistry and Biology
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2024-08-28 , DOI: 10.1021/acs.accounts.4c00320
Peter G Schultz ₁

Affiliation

Chemical synthesis as a tool to control the structure and properties of matter is at the heart of chemistry─from the synthesis of fine chemicals and polymers to drugs and solid-state materials. But as the field evolves to tackle larger and larger molecules and molecular complexes, the traditional tools of synthetic chemistry become limiting. In contrast, Mother Nature has developed very different strategies to create the macromolecules and molecular systems that make up the living cell. Our focus has been to ask whether we can use the synthetic strategies and machinery of Mother Nature, together with modern chemical tools, to create new macromolecules, and even whole organisms with properties not existing in nature. One such example involves reprogramming the complex, multicomponent machinery of ribosomal protein synthesis to add new building blocks to the genetic code, overcoming a billion-year constraint on the chemical nature of proteins. This methodology exploits the concept of bioorthogonality to add unique codons, tRNAs and aminoacyl-tRNA synthetases to cells to encode amino acids with physical, chemical and biological properties not found in nature. As a result, we can make precise changes to the structures of proteins, much like those made by chemists to small molecules and beyond those possible by biological approaches alone. This technology has made it possible to probe protein structure and function in vitro and in vivo in ways heretofore not possible, and to make therapeutic proteins with enhanced pharmacology. A second example involves exploiting the molecular diversity of the humoral immune system together with synthetic transition state analogues to make catalytic antibodies, and then expanding this diversity-based strategy (new to chemists at the time) to drug discovery and materials science. This work ushered in a new nature-inspired synthetic strategy in which large libraries of natural or synthetic molecules are designed and then rationally selected or screened for new function, increasing the efficiency by which we can explore chemical space for new physical, chemical and biological properties. A final example is the use of large chemical libraries, robotics and high throughput phenotypic cellular screens to identify small synthetic molecules that can be used to probe and manipulate the complex biology of the cell, exemplified by druglike molecules that control cell fate. This approach provides new insights into complex biology that complements genomic approaches and can lead to new drugs that act by novel mechanisms of action, for example to selectively regenerate tissues. These and other advances have been made possible by using our knowledge of molecular structure and reactivity hand in hand with our understanding of and ability to manipulate the complex machinery of living cells, opening a new frontier in synthesis. This Account overviews the work in my lab and with our collaborators, from our early days to the present, that revolves around this central theme.

中文翻译：

化学与生物学交叉点的合成

化学合成作为控制物质结构和性质的工具是化学的核心——从精细化学品和聚合物的合成到药物和固态材料。但随着该领域不断发展以解决越来越大的分子和分子复合物，合成化学的传统工具变得有限。相比之下，大自然开发了截然不同的策略来创造构成活细胞的大分子和分子系统。我们的重点是问我们是否可以使用大自然的合成策略和机制，以及现代化学工具来创造新的大分子，甚至具有自然界不存在的特性的整个生物体。其中一个例子涉及对核糖体蛋白质合成的复杂、多组分机制进行重新编程，为遗传密码添加新的构建模块，克服十亿年来对蛋白质化学性质的限制。该方法利用生物正交性的概念，将独特的密码子、tRNA 和氨酰基-tRNA 合成酶添加到细胞中，以编码具有自然界中未发现的物理、化学和生物特性的氨基酸。因此，我们可以对蛋白质的结构进行精确的改变，就像化学家对小分子所做的改变一样，并且超出了仅通过生物学方法可能实现的改变。这项技术使得以迄今为止不可能的方式在体外和体内探测蛋白质结构和功能成为可能，并制造具有增强药理学的治疗性蛋白质。第二个例子涉及利用体液免疫系统的分子多样性以及合成的过渡态类似物来制造催化抗体，然后将这种基于多样性的策略（当时对化学家来说是新的）扩展到药物发现和材料科学。这项工作开创了一种新的受自然启发的合成策略，其中设计了大型天然或合成分子库，然后合理选择或筛选新功能，提高了我们探索化学空间以获得新物理、化学和生物特性的效率。最后一个例子是使用大型化学库、机器人技术和高通量表型细胞筛选来识别可用于探测和操纵细胞复杂生物学的小合成分子，例如控制细胞命运的药物分子。这种方法提供了对复杂生物学的新见解，补充了基因组方法，并可以产生通过新作用机制起作用的新药物，例如选择性再生组织。这些和其他进步是通过利用我们对分子结构和反应性的知识以及我们对活细胞复杂机制的理解和操纵能力而实现的，开辟了合成的新领域。本报告概述了我的实验室以及我们的合作者从早期到现在围绕这一中心主题所做的工作。

更新日期：2024-08-28

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