Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis DOI Creative Commons

Hangke Ma,

Zhaomei Sun,

Lijun Xue

и другие.

ACS Omega, Год журнала: 2023, Номер 8(50), С. 48050 - 48055

Опубликована: Дек. 7, 2023

Over the past three decades, DNA-encoded library (DEL) technologies have become one of most relevant strategies for hit-finding. Recent advances in synthetic methodologies libraries rendered increased chemical space available, but it is unknown how every variety chemistry affects DNA's integrity. Available assays to quantify DNA damage are restricted electrophoresis, ligation efficiency, and mostly qPCR quantification sequencing, which may contain predisposition inconsistency. We developed an external standard method through LC-MS analysis accurately throughout transformations. An assessment was conducted on on-DNA reactions that frequently employed DEL synthesis, these results were compared traditional measurements. Our study provides a simple, practicable, accurate measurement degradation during synthesis. finding reveals substantial disagreement among usual DNA-damaging methods, been largely neglected so far.

Язык: Английский

Agonist Discovery for Membrane Proteins on Live Cells by Using DNA-encoded Libraries DOI
Yiran Huang, Rui Hou, Fong Sang Lam

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(35), С. 24638 - 24653

Опубликована: Авг. 22, 2024

Identifying biologically active ligands for membrane proteins is an important task in chemical biology. We report approach to directly identify small molecule agonists against by selecting DNA-encoded libraries (DELs) on live cells. This method connects extracellular ligand binding with intracellular biochemical transformation, thereby biasing the selection toward agonist identification. have demonstrated methodology three proteins: epidermal growth factor receptor (EGFR), thrombopoietin (TPOR), and insulin (INSR). A ∼30 million a 1.033 billion-compound DEL were selected these targets, novel subnanomolar affinity low micromolar cellular activities been discovered. The INSR activated possibly allosteric site, exhibited clear synergistic effects insulin, downstream signaling pathways. Notably, did not activate insulin-like 1 (IGF-1R), highly homologous whose activation may lead tumor progression. Collectively, this work has developed "functional" selections cell surface provide widely applicable discovery proteins.

Язык: Английский

Процитировано

4
Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets DOI Creative Commons

Yuhan Gui,

Rui Hou, Yuchen Huang

и другие.

Angewandte Chemie, Год журнала: 2025, Номер unknown

Опубликована: Янв. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Язык: Английский

Процитировано

0
Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets DOI Creative Commons

Yuhan Gui,

Rui Hou, Yuchen Huang

и другие.

Angewandte Chemie International Edition, Год журнала: 2025, Номер unknown

Опубликована: Янв. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Язык: Английский

Процитировано

0
Advances in next-generation sequencing (NGS) applications in drug discovery and development DOI
Huihong Wang,

Jiale Huang,

Xianfu Fang

и другие.

Expert Opinion on Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Drug discovery is a complex and multifaceted process driven by scientific innovation advanced technologies. Next-Generation Sequencing (NGS) platforms, encompassing both short-read long-read technologies, have revolutionized the field enabling high-throughput cost-effective analysis of DNA RNA molecules. Continuous advancements in NGS-based technologies enabled their seamless integration across preclinical clinical workflows drug discovery, early-stage target identification, candidate selection, genetically stratified trials, pharmacogenetic studies. This review provides an overview current potential applications development process, including roles novel screening, medication The based on literature retrieval from PubMed Web Science databases between 2018 2024. As advance rapidly, NGS enhances accuracy generates vast datasets. These datasets are extensively integrated with other heterogeneous data systems biology mined using machine learning to extract significant insights, thereby driving progress discovery.

Язык: Английский

Процитировано

0
Photochemical-Promoted Cross-Coupling Reaction of Alkyl Boronate Esters with DNA-Conjugated Aryl Bromides for DNA-Encoded Library Synthesis DOI

Baiyang Mu,

Yiwei Zhang, Xudong Wang

и другие.

Bioconjugate Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 27, 2025

The C(sp2)-C(sp3) cross-coupling reaction is an effective way to increase the C(sp3) content in compound collections for drug discovery, enhancing molecular diversity and offering a unique chemistry starting point. In this study, we report mild, DNA-compatible, off-DNA-inert photochemical inspired by amino radical transfer strategy. This method demonstrates broad substrate scopes DNA-encoded library (DEL) constructions, utilizing commonly available structures on DNA diverse alkyl boronate ester building blocks, which have not been widely applied current DEL chemical space.

Язык: Английский

Процитировано

0
Discovering Cell-targeting Ligands and the Cell Surface Receptors via Selection of DNA-encoded Chemical Libraries (DELs) against Cancer Cells without Predefined Targets DOI Creative Commons

Yuhan Gui,

Rui Hou, Yuchen Huang

и другие.

Опубликована: Фев. 26, 2024

Small molecule ligands that can specifically recognize the surface of cancer cells have wide utilities in diagnosis and treatment. Screening large combinatorial libraries against live is an effective approach to discover cell-targeting ligands. In past decade, DNA-encoded chemical library (DEL or DECL) has become a powerful technology drug discovery been successfully used ligand numerous biological targets. However, nearly all DEL selections had predefined targets, whereas completely unbiased interrogating entire cell remain underexplored. this report, we systematically optimized cell-based selection method perform without A 104.96-million-member was selected MDA-MB-231 MCF7, pair breast lines with high low metastatic properties, respectively, cell-specific small combinations (“clusters”) identified. We further show cluster could be improve binding affinity applied applications including photodynamic therapy targeted delivery. Finally, leveraged DNA tag compounds identified receptor individual targeting cells. Overall, work provides efficient for discovering molecules demonstrated potential DELs as tool biomarker discovery.

Язык: Английский

Процитировано

3
Site-specific DNA post-synthetic modification via fast photocatalytic allylation DOI Creative Commons
Ying Huang, Yixin Zhang, Chenchen Hu

и другие.

Organic Chemistry Frontiers, Год журнала: 2024, Номер 11(16), С. 4408 - 4415

Опубликована: Янв. 1, 2024

Visible light-induced site-specific DNA post-synthetic modification is achieved via fast photocatalytic decarboxylative allylation.

Язык: Английский

Процитировано

3
Mask and Release Strategy‐Enabled Diversity‐Oriented Synthesis for DNA‐Encoded Library DOI Creative Commons
Silin Zhang,

Haiman Zhang,

Xiawen Liu

и другие.

Advanced Science, Год журнала: 2023, Номер 11(6)

Опубликована: Дек. 3, 2023

Abstract An ideal DNA‐encoded library (DEL) selection requires the to consist of diverse core skeletons and cover chemical space as much possible. However, lack efficient on‐DNA synthetic approaches toward has greatly restricted diversity DEL. To mitigate this issue, work disclosed a “Mask & Release” strategy streamline challenging skeleton synthesis. N ‐phenoxyacetamide is used masked phenol versatile directing group mediate diversified DNA‐compatible C‐H functionalization, introducing 1st‐dimensional at defined site, simultaneously releasing functionality, which can facilitate introduction 2nd diversity. This not only provides set syntheses DNA‐conjugated drug‐like such ortho ‐alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also paradigm for method development.

Язык: Английский

Процитировано

9
DNA-encoded librariesvialate-stage functionalization strategies: a review DOI
Rajesh Sahu, S. B. S. Yadav,

Suvadeep Nath

и другие.

Chemical Communications, Год журнала: 2023, Номер 59(41), С. 6128 - 6147

Опубликована: Янв. 1, 2023

The hit finding strategy in drug discovery has undergone a tremendous change the past decade with advent of DNA-encoded libraries diverse chemical libraries.

Язык: Английский

Процитировано

8
A photocatalytic traceless C–N bond formation/cleavage strategy enabling the use of (α-chiral) alkyl aldehydes as deoxygenative (chiral) alkyl radical equivalents DOI

Hanyang Bao,

Limeng Zheng,

Qian Liu

и другие.

Organic Chemistry Frontiers, Год журнала: 2023, Номер 10(22), С. 5551 - 5558

Опубликована: Янв. 1, 2023

α-Chiral alkyl aldehydes were used as deoxygenative chiral radical equivalents for the first time in 4-CzIPN-catalyzed alkylation/cyclization of 2-biphenylisonitriles with under photocatalytic conditions.

Язык: Английский

Процитировано

8