Design and Application of a DNA-Encoded Macrocyclic Peptide Library

Zhu, Zhengrong; Shaginian, Alex; Grady, LaShadric C.; O’Keeffe, Thomas; Shi, Xiangguo; Davie, Christopher P.; Simpson, Graham L.; Messer, Jeffrey A.; Evindar, Ghotas; Bream, Robert N.; Thansandote, Praew; Prentice, Naomi R.; Mason, Andrew M.; Pal, Siladitya

doi:10.1021/acschembio.7b00852

Cited by 87 publications

(85 citation statements)

References 35 publications

(60 reference statements)

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“…In conclusion, we presented a robust procedure for the photoredox‐mediated addition of α‐amino acid‐derived radicals to various DNA‐tagged radical acceptors, which proceeds under mild, DEL‐compatible conditions. Given that a plethora of N ‐protected α‐amino acids is either commercially available or can be readily prepared, this substrate class is of great value for combinatorial chemistry . Moreover, Boc‐protected amines can be easily deprotected in a DNA‐compatible manner to enable the next chemistry cycle, which is why N ‐Boc‐α‐amino acids are already routinely used as building blocks for the preparation of DELs.…”

Section: Methodsmentioning

confidence: 99%

Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids

et al. 2018

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A new procedure for the photoredox-mediated conjugate addition of radicals that can be conveniently generated from α-amino acids to DNA-tagged Michael acceptors and styrenes is presented. This C(sp )-C(sp ) coupling tolerates a broad array of structurally diverse radical precursors, including all of the 20 proteinogenic amino acids. Importantly, this reaction proceeds under mild conditions and in DNA-compatible aqueous media. Furthermore, the presented reaction conditions are compatible with DNA, making this reaction platform well suited for the construction of DNA-encoded libraries. The scope and limitations of the chemistry are discussed herein along with proposals for how this methodology might be used to construct DNA-encoded libraries.

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Section: Methodsmentioning

confidence: 99%

Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids

et al. 2018

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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.…”

mentioning

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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“…Fully synthetic approaches that follow a split‐and‐pool workflow have been employed wherein coupling of each monomer is followed by attachment of a unique DNA barcode. Cyclization can then be initiated by activating complementary reactive handles that are installed during synthesis, such as azide‐alkyne groups . This strategy was recently used to generate a library of more than 10 12 macrocycles consisting of natural and unnatural amino acid building blocks 4–20 units in length.…”

Section: Hijacking the Ribosome: Co‐translational Nucleic‐acid Barcodmentioning

confidence: 99%

“…Similar to the small-molecule drug screening platforms described above,much effort has gone into creating large and diverse libraries of nucleic acid-barcoded peptide macrocycles.Fully synthetic approaches that follow asplit-and-pool workflow have been employed wherein coupling of each monomer is followed by attachment of au nique DNA barcode.C yclization can then be initiated by activating complementary reactive handles that are installed during synthesis,s uch as azide-alkyne groups. [70] This strategy was recently used to generate al ibrary of more than 10 12 macrocycles consisting of natural and unnatural amino acid building blocks 4-20 units in length. One shortcoming related to this approach is that the selection process cannot be iterated to enrich for specific binders.T oc ircumvent this problem, the Liu laboratory has extended DNAt emplated synthesis to include DNA-conjugated building blocks that may be cyclized through Wittig olefination after the final building-block coupling step.…”

Section: Reviewsmentioning

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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Design and Application of a DNA-Encoded Macrocyclic Peptide Library

Cited by 87 publications

References 35 publications

Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids

Employing Photoredox Catalysis for DNA‐Encoded Chemistry: Decarboxylative Alkylation of α‐Amino Acids

DNA‐encoded chemical libraries – achievements and remaining challenges

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

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