A DNA-templated synthesis of encoded small molecules by DNA self-assembly

Cao, Chunmei; Zhao, Peng; Li, Ze; Chen, Zitian; Huang, Yanyi; Bai, Yu; Li, Xiaoyu

doi:10.1039/c4cc03380a

Cited by 30 publications

(27 citation statements)

References 33 publications

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“…The YoctoReactor has been used to generate libraries comprising more than 10 7 unique members. 47 This method, as well as a related approach described by Cao and co-workers, 41 simplifies adapter design by decoupling the DNA domain encoding BB identity from that directly involved in DNA templating ( Figure 10 c). However, in both cases a BB requires a different adapter for each position in the product.…”

Section: Combinatorial Synthesis By Dtsmentioning

confidence: 99%

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

2017

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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 ha...

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Section: Combinatorial Synthesis By Dtsmentioning

confidence: 99%

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

2017

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“…DNA encoded library (DEL) technology allows for facile generation and screening of extremely large numbers of drug-like molecules. − Numerous literature reports illustrate the value of the technology including the discovery of LFA-1, ADAMTS-5, RIP3 kinase, BCATm, InhA, SIRT1–3, Wip1 phosphatase, and sEH inhibitors. DNA encoded libraries (DELs) are commonly synthesized via split-and-pool chemistry, − although a variety of alternative methodologies have been reported. − Regardless of the method of synthesis, the technology results in the generation of complex mixtures of DNA conjugates. Each library member consists of a small-molecule moiety covalently tethered to a DNA sequence.…”

Section: Introductionmentioning

confidence: 99%

“…The DNA sequence, or barcode, encodes the protocol for the multistep chemical synthesis of the attached small molecule. Generally, the multistep synthesis consists of aqueous and DNA-compatible reactions, which allow access to drug-like small molecules. − It is generally not possible to remove unreacted starting materials or byproducts during library synthesis or to quantify the yields of the products and byproducts. − Thus, the final population of library members with a particular barcode will include many related but different small molecules . The ratios of the different products is dictated by the synthetic yields at each step of the multistep synthesis.…”

Section: Introductionmentioning

confidence: 99%

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Satz

2016

ACS Comb. Sci.

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Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

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“…By tuning the nature of the released functional molecule, so as it acts either as a reporter or as an active therapeutic agent, this strategy can be of interest for both sensing and drug release purposes, respectively (Figure b) . Furthermore, DTS has been exploited to program the synthesis of complex molecules, such as macrocycles, oligomers and nonnatural small molecules, via multistep reactions in a single pot. Autonomous systems were also developed, such as a mechanical arrangement in which a DNA walker triggers reactions as it moves along a nucleic acid track, conceptually mimicking a ribosome.…”

Section: Chemical Synthesis On Dna‐based Supportsmentioning

confidence: 99%

Programming DNA‐Based Systems through Effective Molarity Enforced by Biomolecular Confinement

Rossetti

Bertucci

Patiño

et al. 2020

Chemistry A European J

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The fundamental concept of effective molarity is observed in av ariety of biological processes, such as protein compartmentalization within organelles, membrane localization and signaling paths. To controlm olecular encountering and promotee ffective interactions, nature places biomolecules in specific sites inside the cell in order to generate a high, localized concentration different from the bulk concentration. Inspired by this mechanism, scientists have artificially recreated in the lab the same strategy to actuate and control artificial DNA-based functional systems. Here, it is discussed how harnessing effective molarity has led to the development of an umber of proximity-induced strategies, with applications ranging from DNA-templated organic chemistry and catalysis, to biosensing and protein-supported DNA assembly.

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A DNA-templated synthesis of encoded small molecules by DNA self-assembly

Cited by 30 publications

References 33 publications

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

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

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Programming DNA‐Based Systems through Effective Molarity Enforced by Biomolecular Confinement

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