Abstract
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.