Abstract
ConspectusPrecise 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.
Highlights
Two centuries of research has furnished chemists with the ability to synthesize a huge variety of molecular architectures based on organic and inorganic components and to create materials with new functions ranging from therapeutics to solar cells
We recently reported a second example of autonomous DNA-templated synthesis (DTS), using a hybridization chain reaction (HCR) to bring BBs into proximity with the growing oligomer in sequence[22] (Figure 8c, lower scheme)
Using this method we have so far been able to demonstrate the construction of decamers which, with those synthesized using the templated parallel method described above, are currently the longest oligomers constructed by DTS.[43]
Summary
Two centuries of research has furnished chemists with the ability to synthesize a huge variety of molecular architectures based on organic and inorganic components and to create materials with new functions ranging from therapeutics to solar cells. Adapters are distinguished by the unhybridized toehold domain used to drive their eventual displacement so they can all be designed to be the same length Using this method we have so far been able to demonstrate the construction of decamers which, with those synthesized using the templated parallel method described above, are currently the longest oligomers constructed by DTS.[43] control over reaction sequence requires the sequential addition of BBs. A more sophisticated system (Figure 9b) uses the serial addition of instruction strands to control reactions within a vessel containing a mixture of all BBs.[44] Neither method lends itself to encoding the identity of the product in the final DNA tag, . Since comparable library sizes are achievable with both, it is perhaps not surprising that the adoption of DTS by the pharmaceutical industry has been slower, in spite of the promise shown by functional selection experiments.[4]
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