Small-molecule discovery through DNA-encoded libraries

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(9), P. 699 - 722

Published: June 16, 2023

Language: Английский

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DNA‐Encoded Libraries: Towards Harnessing their Full Power with Darwinian Evolution

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(9)

Published: Dec. 2, 2022

Abstract DNA‐encoded library (DEL) technologies are transforming the drug discovery process, enabling identification of ligands at unprecedented speed and scale. DEL makes use libraries that orders magnitude larger than traditional high‐throughput screens. While a DNA tag alludes to genotype–phenotype connection is exploitable for molecular evolution, most work in field performed with where serves as an amplifiable barcode but does not allow “translation” into synthetic product it linked to. In this Review, we cover enable genetic molecules, both biochemically chemically, explore how can be used harness Darwinian evolutionary pressure.

Language: Английский

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Evolution of chemistry and selection technology for DNA-encoded library

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(2), P. 492 - 516

Published: Oct. 11, 2023

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and non-self-replicating phenotypes, generating a diverse world. In analogy with biological world, DEL world can evolve by using central dogma, wherein DNA replicates PCR reactions to amplify genetic codes, sequencing transcripts information, DNA-compatible synthesis translates into phenotypes. Importantly, is key expanding space. Besides, evolution-driven selection system pushes chemicals under selective pressure, i.e., desired strategies. this perspective, we summarized recent advances in synthetic toolbox panning strategies, which will shed light on drug discovery harnessing vitro evolution via DEL.

Language: Английский

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Encoding and display technologies for combinatorial libraries in drug discovery: The coming of age from biology to therapy

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3362 - 3384

Published: April 10, 2024

Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments promising tools pharmaceutical hit due their high efficiency, throughput, resource minimization. This review systematically summarizes the development history, typology, prospective applications of displayed technologies, including phage display, ribosomal mRNA yeast cell one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, new peptide-encoded examples preclinical clinical translation. We discuss progress novel targeted therapeutic agents, covering spectrum small-molecule inhibitors nonpeptidic macrocycles linear, monocyclic, bicyclic peptides, in addition antibodies. also address pending challenges future prospects drug discovery, size libraries, advantages disadvantages technology, translational potential, market space. intended establish comprehensive high-throughput strategy researchers developers.

Language: Английский

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Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(4), P. 543 - 555

Published: Feb. 7, 2024

Language: Английский

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Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(15)

Published: Feb. 12, 2024

Abstract Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage great importance expanding the toolbox. We report first selenium‐nitrogen exchange (SeNEx) reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which inspired by biochemical SeNEx Ebselen cysteine (Cys) residue Se−S). formed selenoalkyne connection readily elaborated, thus endowing this multidimensional diversity. Besides, modular, predictable, high‐yielding, features fast kinetics (k2≥14.43 M −1 s ), excellent group compatibility, works well at miniaturization (nanomole‐scale), opening up many interesting opportunities organo‐Se synthesis bioconjugation, as exemplified sequential (coupled ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) sulfur‐fluoride (SuFEx)), selenomacrocycle synthesis, nanomole‐scale Se‐containing natural product library DNA‐encoded (DEL), late‐stage peptide modification ligation, multiple functionalization proteins. These results indicated that useful developments, established will serve transformative platform in multidisciplinary fields such synthetic chemistry, material science, chemical biology, medical drug

Language: Английский

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Innovative, combinatorial and high-throughput approaches to degrader synthesis

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4838 - 4861

Published: Jan. 1, 2024

In this review we highlight how the synthesis of degraders has evolved in recent years, particular application high-throughput chemistry and screening approaches such as D2B DEL technologies to expedite discovery timelines.

Language: Английский

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The Evolution of Nucleic Acid Nanotechnology: From DNA Assembly to DNA‐Encoded Library

Small Methods, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Deoxyribonucleic acid (DNA), a fundamental biomacromolecule in living organisms, serves as the carrier of genetic information. Beyond its role encoding biological functions, DNA's inherent ability to hybridize through base pairing has opened new avenues for application sciences. This review introduces DNA nanotechnology and DNA‐encoded library (DEL), highlights their shared design principles related assembly. First, foundational overview structural nanotechnology, including strategies historical development is provided. Subsequently, various approaches are examined dynamic from strand displacement reactions DNA‐templated polymer synthesis. Second, how principle assembly facilitated diverse formats self‐assembly‐based DEL synthesis, DNA‐template (DTS), template‐mediated proximity induction effects examined. These advancements all underpinned by unique property Finally, this summarizes common terms methodology design. Additionally, potential synergies explored between these two technologies, envisioning future applications where they can be combined create more versatile exquisite functionalities.

Language: Английский

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Access to N-α-deuterated amino acids and DNA conjugates via Ca(II)-HFIP-mediated reductive deutero-amination of α-oxo-carbonyl compounds

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 20, 2025

The development of practical and selective strategies for deuterium incorporation to construct deuterated molecules, particularly deuterium-labeled amino acids, has become as a growing focus basic research, yet it remains formidable challenge. Herein, we present bioinspired calcium-HFIP-mediated site-selective reductive deutero-amination α-oxo-carbonyl compounds with amines. Utilizing d2-Hantzsch ester the source, this reaction attains remarkable deuteration efficiency (> 99% deuteration). It enables synthesis N-α-deuterated acid motifs wide range functionality, evidenced by over 130 examples. method exhibits compatibility diverse substrates, such peptides, drug natural products bearing different substituents. Moreover, application strategy in DNA-tagged acids/peptides been demonstrated. This work offers an efficient innovative solution chemistry holds substantial potential organic synthesis, medicinal chemistry, chemical biology.

Language: Английский

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Direct Selection of DNA-Encoded Libraries for Biased Agonists of GPCRs on Live Cells

JACS Au, Journal Year: 2023, Volume and Issue: 3(4), P. 1076 - 1088

Published: March 22, 2023

G protein-coupled receptors (GPCRs) are the largest superfamily of human membrane target proteins for approved drugs. GPCR ligands can have a complex array pharmacological activities. Among these activities, biased agonists potential to serve as both chemical probes understand specific aspects receptor signaling and therapeutic leads with more specific, desired activity. Challenges exist, however, in development new activators due, part, low throughput traditional screening approaches. DNA-encoded libraries (DELs) dramatically improve drug discovery by allowing collective selection, rather than discrete screening, large compound libraries. The use DELs has been largely limited affinity-based selections against purified protein targets, which identify binders only. Herein, we report split complementation approach that allows direct identification DNA-linked molecules induce dimerization two proteins. We used this selection DEL opioid GPCRs on living cells small possess function activation either β-arrestin or pathways. This was applied δ-, μ-, κ-opioid enabled [66,66], selective, G-protein-biased agonist (EC50 = 100 nM, Emax 82%, Gi bias factor 6.6). should be generally applicable inducers from expand utility enrich biochemical function.

Language: Английский

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