Strategies for developing DNA-encoded libraries beyond binding assays

Nature Chemistry, Год журнала: 2022, Номер 14(2), С. 129 - 140

Опубликована: Фев. 1, 2022

Язык: Английский

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

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(3), С. 2122 - 2131

Опубликована: Янв. 8, 2024

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

Язык: Английский

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The expanding reaction toolkit for DNA-encoded libraries

Bioorganic & Medicinal Chemistry Letters, Год журнала: 2021, Номер 51, С. 128339 - 128339

Опубликована: Авг. 31, 2021

Over the past decade, DNA-encoded libraries (DELs) have emerged as a leading platform for small molecule drug discovery among pharmaceutical companies, biotech companies and academic hunters alike. This revolutionary technology has tremendous potential that is yet to be fully realized, exploration of therapeutically relevant chemical space fueled by ever-expanding repertoire DNA-compatible reactions used construct libraries. Advances in direct coupling reactions, like photo-catalytic cross couplings, unique cyclizations such formation 1,2,4-oxadiazoles, new functional group transformations are valuable contributions DEL reaction toolkit, indicate where future development efforts should focus order maximize productivity DELs.

Язык: Английский

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The Time and Place for Nature in Drug Discovery

JACS Au, Год журнала: 2022, Номер 2(11), С. 2400 - 2416

Опубликована: Окт. 14, 2022

The case for a renewed focus on Nature in drug discovery is reviewed; not terms of natural product screening, but how and why biomimetic molecules, especially those produced by processes, should deliver the age artificial intelligence screening vast collections both vitro silico. declining product-likeness licensed drugs consequent physicochemical implications this trend context current practices are noted. To arrest these trends, logic seeking new bioactive agents with enhanced mimicry considered; notably that molecules constructed proteins (enzymes) more likely to interact other (e.g., targets transporters), notion validated products. Nature's finite number building blocks their interactions necessarily reduce potential numbers structures, yet enable expansion chemical space inherent diversity physical characteristics, pertinent property-based design. feasible variations motifs considered expanded encompass pseudo-natural products, leading further logical step harnessing bioprocessing routes access them. Together, offer opportunities enhancing mimicry, thereby bringing innovation synthesis exploiting characteristics recognition processes. computational guidance help identifying binding commonalities route map opportunity design tailored "organic/biological" rather than purely "synthetic" structures. prototype structures pay dividends disposition efficacy while inherently enabling greener sustainable manufacturing techniques.

Язык: Английский

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The Growing Importance of Chirality in 3D Chemical Space Exploration and Modern Drug Discovery Approaches for Hit-ID

ACS Medicinal Chemistry Letters, Год журнала: 2021, Номер 12(8), С. 1220 - 1229

Опубликована: Июль 16, 2021

Modern-day drug discovery is now blessed with a wide range of high-throughput hit identification (hit-ID) strategies that have been successfully validated in recent years, particular success coming from screening, fragment-based lead discovery, and DNA-encoded library screening. As screening efficiency throughput increases, this enables the viable exploration increasingly complex three-dimensional (3D) chemical structure space, realistic chance identifying highly specific ligands increased target specificity reduced attrition rates preclinical clinical development. This minireview will explore impact an improved design multifunctionalized, sp3-rich, stereodefined scaffolds on (virtual) 3D space requirements for different hit-ID technologies.

Язык: Английский

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Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis

Accounts of Chemical Research, Год журнала: 2023, Номер 56(3), С. 385 - 401

Опубликована: Янв. 19, 2023

ConspectusDNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination other technologies such as high-throughput (HTS), fragment-based lead generation, structure-based drug design, has the to transform how discovery carried out. DELT hybrid which chemically synthesized compounds are linked unique genetic tags (or "barcodes") contain readable information. In this way, millions billions building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against target single experiment. Polymerase chain reaction (PCR) amplification next-generation sequencing (NGS) analysis sequence oligonucleotides DNA tag used identify those ligands high affinity for target. innovative fusion chemical was conceived 1992 by Brenner Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381–5383) under accelerated development implementation synthetic techniques protocols compatible DNA. fact, compatibility key parameter increasing chances ligand, central focus been transformations transition robust synthesis. Because sole use amplifiable barcode, its structural integrity during process mandatory. As such, these sensitive, polyfunctional substrates typically requires aqueous solutions within defined pH temperature ranges, considered notable challenge DEL synthesis.Using low-energy visible light driving force promote attractive alternative classical methods, it important well-established tool forging bonds way radical intermediates. Recent advances field photocatalysis extraordinary, powerful research arena still continuous development. Several applications taking advantage mild conditions photoinduced have directed toward synthesis, allowing expansion space available evaluation on-DNA. There no doubts visible-light-driven reactions become one most approaches DELT, given easy they provide construct challenges achieve equal success protocols.Key characteristics photocatalytic include short times efficiency, translate into retention integrity. Account, we describe recent diversification prepared on-DNA, highlighting amenability employed preserving structure molecules. We demonstrate from our group applicability summary table containing all methods reported date demonstrating their aspects scope, applications, compatibilities. With information, practitioners provided compelling reasons developing/choosing applications.

Язык: Английский

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Enzymatic Bioconjugation: A Perspective from the Pharmaceutical Industry

JACS Au, Год журнала: 2023, Номер 3(5), С. 1267 - 1283

Опубликована: Май 4, 2023

Enzymes have firmly established themselves as bespoke catalysts for small molecule transformations in the pharmaceutical industry, from early research and development stages to large-scale production. In principle, their exquisite selectivity rate acceleration can also be leveraged modifying macromolecules form bioconjugates. However, available face stiff competition other bioorthogonal chemistries. this Perspective, we seek illuminate applications of enzymatic bioconjugation an expanding palette new drug modalities. With these applications, wish highlight some examples current successes pitfalls using enzymes along pipeline try illustrate opportunities further development.

Язык: Английский

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

Nature Chemistry, Год журнала: 2024, Номер 16(4), С. 543 - 555

Опубликована: Фев. 7, 2024

Язык: Английский

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Digital Barcodes for High-Throughput Screening

Chem & Bio Engineering, Год журнала: 2024, Номер 1(1), С. 2 - 12

Опубликована: Янв. 26, 2024

High-throughput screening is an indispensable technology in drug discovery, cancer therapy, and disease diagnosis, it could greatly reduce time cost, reagent consumption, labor expense. Here, four high-throughput methods with high sensitivity accessibility are discussed detail. Fluorescence, DNA, heavy metal, nonmetal isotope barcodes, which generally label antibodies, proteins, saccharides to identify cells, detected by flow cytometry, second-generation DNA sequencing, mass second-ion spectrometry, respectively. Encoding binary information labeling individual cells performing the characterization of together, identifying result belonging via barcodes main steps for screening. Applications digital both vitro vivo tests described detail, their advantages disadvantages also summarized. has provided a powerful platform widely accessible multidisciplinary studies sped up progress therapy.

Язык: Английский

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Innovative, combinatorial and high-throughput approaches to degrader synthesis

Chemical Society Reviews, Год журнала: 2024, Номер 53(10), С. 4838 - 4861

Опубликована: Янв. 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.

Язык: Английский

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