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Cited by 92Advanced biosensing and bioanalysis techniquesChemical Synthesis and AnalysisAdvanced Polymer Synthesis and Characterization

The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery

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O’Reilly, Rachel K., Turberfield, Andrew J., Wilks, Thomas R.·2017·Accounts of Chemical Research
DOI 10.1021/acs.accounts.7b00280PMC PMC5746846
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Abstract

Conspectus: 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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  • Several DNA-templated reactions with longer probes proceed within minutes at very low concentrations, benefiting from high effective concentrations in stable hybridization complexes.

    “In contrast, several DNA-templated reactions with longer probes have been shown to proceed within minutes at very low concentrations, benefiting from high effective concentrations in stable hybridization complexes.18−20”

    From Sequencing of <scp>d</scp>/<scp>l</scp>-DNA and XNA by Templated-Synthesis (2025) · cites this paper as [20]

    The Introduction (page unavailable) says DNA hybridization brings reactive groups close together, increasing their effective local concentration and reaction rate even when bulk concentrations are low (nM). The passages do not establish that several reactions using longer probes proceed within minutes, or specify stable hybridization complexes as the condition for that timing. (LLM, conf=0.85)

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Authors
O’Reilly, R. K., Turberfield, A. J., & Wilks, T. R.
Affiliations
  • University of Warwick (GB)
  • University of Oxford (GB)
Corresponding author
  • O’Reilly, Rachel K.
  • Turberfield, Andrew J.
  • Wilks, Thomas R.
ORCID
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2017-09-15
Volume
50
Issue
10
Pages
2496-2509
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/acs.accounts.7b00280
PMC
PMC5746846
OpenAlex
W2755034651
Cited by
92
References
3
Citations by year
2026: 5 · 2025: 12 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 2 · 2020: 13 · 2019: 9 · 2018: 6 · 2017: 1
FWCI
3.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Accounts of Chemical Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
Funders
  • H2020 European Research Council (NA)
  • Engineering and Physical Sciences Research Council (EP/F008597/1, EP/F009062/2, EP/F055803/1, EP/F056605/1)
  • Biotechnology and Biological Sciences Research Council (BB/J00054X/1)
  • Royal Society (NA)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Physical Sciences › Chemistry › Organic Chemistry › Advanced Polymer Synthesis and Characterization
Keywords
DNA-templated synthesis, combinatorial libraries, DNA hybridization, chemical space exploration, materials discovery, mRNA display, library screening, PCR, drug discovery, DNA nanobots, DNA nanomotors
MeSH terms
DNA, Nucleic Acid Hybridization, Combinatorial Chemistry Techniques, Small Molecule Libraries

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