Small-molecule discovery through DNA-encoded libraries

Peterson, Alexander A.; Liu, David R.

doi:10.1038/s41573-023-00713-6

Cited by 67 publications

(25 citation statements)

References 162 publications

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“…may slightly vary. Recently, bioconjugation chemistry that complies with the standards of DNA compatibility and creates drug-like scaffolds is valuable for DNA-encoded chemical library (DEL) construction and further selection to isolate bioactive molecules. − Considering the diverse transformation of the tetrazole moiety, our group has previously explored DNA-compatible chemical reactions focused on tetrazoles. We reported the application of 1,3-dipolar cycloaddition reaction between tetrazoles and alkenes to assemble pyrazoline scaffold meaningful DELs .…”

Section: Introductionmentioning

confidence: 99%

Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Zhang,

Liu,

et al. 2024

J. Am. Chem. Soc.

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Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed as a bioorthogonal photoclick handle for 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity with carboxylic acids, serving as a versatile bioconjugation and photoaffinity labeling probe. In this study, we unexpectedly discovered and validated the photoreactivity between tetrazole and primary amine to afford a new 1,2,4-triazole cyclization product. Given the significance of functionalized Nheterocycles in medicinal chemistry, we successfully harnessed the serendipitously discovered reaction to synthesize both pharmacologically relevant DNA-encoded chemical libraries (DELs) and small molecule compounds bearing 1,2,4-triazole scaffolds. Furthermore, the mild reaction conditions and stable 1,2,4-triazole linkage found broad application in photoinduced bioconjugation scenarios, spanning from intramolecular peptide macrocyclization and templated DNA reaction cross-linking to intermolecular photoaffinity labeling of proteins. Triazole cross-linking products on lysine side chains were identified in tetrazole-labeled proteins, refining the comprehensive understanding of the photo-cross-linking profiles of tetrazole-based probes. Altogether, this tetrazoleamine bioconjugation expands the current bioconjugation toolbox and creates new possibilities at the interface of medicinal chemistry and chemical biology.

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Section: Introductionmentioning

confidence: 99%

Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Zhang,

Liu,

et al. 2024

J. Am. Chem. Soc.

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“…DNA-encoded chemical libraries (DELs) are now fully integrated in comprehensive drug discovery campaigns in both academia and industry. , They are composed of synthetic compounds linked to a unique oligonucleotide that serves as an identification barcode. , This labeling strategy allows for the screening of thousands to billions of small molecules simultaneously, facilitating ligand discovery by accelerating experimental timelines and reducing costs . Binders are typically selected by incubating DELs with a desired target immobilized on a solid support .…”

Section: Introductionmentioning

confidence: 99%

Asymmetry of Dual-Display DNA-Encoded Chemical Libraries

Plais,

Trachsel,

Scheuermann

2024

Bioconjugate Chem.

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While dual-display DNA-encoded chemical libraries (DELs) are increasingly employed for ligand discovery, some of their fundamental properties have not yet been studied in-depth. Aided with fluorescence polarization experiments, we demonstrate that dual-display DELs are intrinsically asymmetrical entities, and we deduce practical guidelines to perform better-informed on-DNA hit validation from these libraries.

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“…The optimization of hits is a crucial phase in the exploration and development of novel chemical compounds through DELs. Several effective methods for optimizing DEL hits have been employed, such as virtual screening, SAR analysis, and guidance from cocrystal structures. , More importantly, selections using library retooling is considered another valuable strategy to enhance the discovery of active ligands due to the DEL inherent advantages. − For example, using two generations of directed DELs, Dykhuizen et al reported hit identification and subsequently further optimization to increase potency, cell permeability, and selectivity …”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach

Qin,

Feng,

Zhao

et al. 2024

J. Med. Chem.

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The DNA-encoded library (DEL) is a powerful hit generation tool for chemical biology and drug discovery; however, the optimization of DEL hits remained a daunting challenge for the medicinal chemistry community. In this study, hit compounds targeting the WIN binding domain of WDR5 were discovered by the initial three-cycle linear DEL selection, and their potency was further enhanced by a cascade DEL selection from the focused DEL designed based on the original first run DEL hits. As expected, these new compounds from the second run of focused DEL were more potent WDR5 inhibitors in the protein binding assay confirmed by the off-DNA synthesis. Interestingly, selected inhibitors exhibited good antiproliferative activity in two human acute leukemia cell lines. Taken together, this new cascade DEL selection strategy may have tremendous potential for finding high-affinity leads against WDR5 and provide opportunities to explore and optimize inhibitors for other targets.

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Small-molecule discovery through DNA-encoded libraries

Cited by 67 publications

References 162 publications

Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Asymmetry of Dual-Display DNA-Encoded Chemical Libraries

Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach

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