DNA-encoded chemical libraries: foundations and applications in lead discovery

Zimmermann, Gunther; Neri, Dario

doi:10.1016/j.drudis.2016.07.013

Cited by 116 publications

(78 citation statements)

References 52 publications

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“…In 2004, three groups independently described that DNA-encoded chemical libraries can be synthesized and screened without beads [10][11][12]. Since then, in virtually all cases, DNA-encoded chemical libraries are synthesized and screened by direct coupling of organic molecules to the corresponding DNA tags [1,[13][14][15][16][17][18][19][20][21]. There are, however, multiple strategies for the synthesis of encoded libraries, as illustrated in a later section of this manuscript.…”

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confidence: 99%

DNA‐encoded chemical libraries – achievements and remaining challenges

et al. 2018

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Edited by Wilhelm JustDNA-encoded chemical libraries (DECLs) are collections of compounds, individually coupled to DNA tags serving as amplifiable identification barcodes. Since individual compounds can be identified by the associated DNA tag, they can be stored as a mixture, allowing the synthesis and screening of combinatorial libraries of unprecedented size, facilitated by the implementation of split-and-pool synthetic procedures or other experimental methodologies. In this review, we briefly present relevant concepts and technologies, which are required for the implementation and interpretation of screening procedures with DNA-encoded chemical libraries. Moreover, we illustrate some success stories, detailing how novel ligands were discovered from encoded libraries. Finally, we critically review what can realistically be achieved with the technology at the present time, highlighting challenges and opportunities for the future.

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DNA‐encoded chemical libraries – achievements and remaining challenges

et al. 2018

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“…The use of DNA encoding for general solution-phase small-molecule libraries suitable for in vitro selection was conceived and developed over the next decade 5, 6 . Since then, the field of selectable DNA-encoded libraries has greatly expanded to include a wide variety of small-molecule and synthetic polymer structures, as well as a number of different strategies to ensure the correspondence between a library member’s structure and the attached DNA barcode sequence, including DNA-templated synthesis, DNA routing, DNA tagging (ligation of DNA barcodes after each synthesis step), and variants and combinations of these concepts 7–16 . Selections using DELs are typically conducted by incubating an immobilized or epitope-tagged target with the library, washing unbound library members away from library members with target affinity, and isolating the latter by eluting or denaturing the target, or by adding an excess of a known ligand or free target 15–17 .…”

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Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

et al. 2018

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DNA-encoded libraries have emerged as a widely used resource for discovery of bioactive small molecules and offer substantial advantages compared to conventional small-molecule libraries. Here we developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20×20×20×80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small-molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme (IDE) affinity resulted in novel IDE inhibitors including one of unusual potency and novel macrocycle stereochemistry (IC50 = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined, and cost-effective tools for bioactive small-molecule discovery.

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“…[36] Densely functionalized nucleic-acid polymers are DNApolymers in which every third nucleotide contains af unctionalized base moiety.T oa ssemble such libraries in as ingle-pot, functionalized trinucleotides (or codons) are prepared and hybridized with alibrary of singlestranded DNAt emplates that present unique codon reading frames.After synthetic-codon annealing, DNAl igase is used to ligate the codons and create the functionalized nucleic-acid polymer.Excellent reviews further describing these and other DNA-encoded small molecule library technologies and their success in drug discovery can be found elsewhere. [38] 3. Hijacking the Ribosome:C o-Translational Nucleic-Acid Barcoding of Proteins in vitro Avast majority of proteins and peptide macrocycles are out of reach for the synthetic chemist, and thus not amenable to the chemical approaches described for DNA-encoded small-molecule library assembly.T herefore,u nique methodologies are required to create DNA-encoded biomolecular libraries,w hich are powerful tools for the high-throughput analysis of protein function, interaction networks,and ligand discovery and characterization.…”

Section: Dna-templated Chemistrymentioning

confidence: 99%

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

Liszczak

Muir

2019

Angew Chem Int Ed

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The emergence of high-throughput DNA sequencing technologies sparked an immediate revolution in the field of genomics that has rippled into many branches of the life and physical sciences. The remarkable sensitivity, specificity, throughput, and multiplexing capacity that are inherent to massively parallel DNA sequencing have since motivated its use as a broad-spectrum molecular counter in small molecule and peptide-based inhibitor discovery, high-throughput biochemistry, protein and cellular detection and diagnostics, and even materials science. A key aspect of extrapolating DNA sequencing to 'non-traditional' applications is the underlying need to append nucleic acid barcodes to entities of interest. In this review, we describe the chemical and biochemical approaches that have enabled facile nucleic acid barcoding of proteinaceous and non-proteinaceous materials, and provide exciting examples of downstream technologies that have been made possible by DNA-encoded molecules. Considering that commercially available high-throughput sequencers were first released less than 15 years ago, we believe related applications will continue to mature for years to come, and close by proposing potential new frontiers to support this assertion.

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DNA-encoded chemical libraries: foundations and applications in lead discovery

Cited by 116 publications

References 52 publications

DNA‐encoded chemical libraries – achievements and remaining challenges

DNA‐encoded chemical libraries – achievements and remaining challenges

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

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