Conspectus
Chemical synthesis as a tool
to control the
structure and properties
of matter is at the heart of chemistryfrom 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.
