Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 Mpro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants DOI
Xu Wang, Dimitar Gotchev, Kristi Fan

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19623 - 19667

Published: Oct. 25, 2024

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. main protease (M

Language: Английский

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

Yu Fan,

Ruibing Feng, Xinya Zhang

et al.

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

Citations

12
Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation DOI
Wei Hou, Yiyuan Zhang,

Fuchao Huang

et al.

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

Citations

10
Access to N-α-deuterated amino acids and DNA conjugates via Ca(II)-HFIP-mediated reductive deutero-amination of α-oxo-carbonyl compounds DOI Creative Commons
Haoran Li,

Yuwei Liu,

Silin Zhang

et al.

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

Citations

1
Synthesis of Diacylhydrazine Derivatives Based on Tetrazole-Focused DNA-Encoded Library DOI
Juan Zhang, Jinlu Liu, Gong Zhang

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(5), P. 1094 - 1099

Published: Jan. 26, 2024

Utilizing already existing DNA-encoded libraries (DELs) for the generation of a distinct DEL represents an expedited strategy expanding chemical space. Herein, we leverage unique photoreactivity tetrazoles to synthesize diacylhydrazines on DNA. Widely available carboxylic acids serving as building blocks were employed under mild photomediated reaction conditions, affording diverse DNA-conjugated diacylhydrazines. This methodology also demonstrates robustness in DEL-compatible synthesis and facilitates preparation oligonucleotide-based probes.

Language: Английский

Citations

6
Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets DOI
Guixian Zhao, Mengping Zhu, Yangfeng Li

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(6), P. 725 - 740

Published: May 16, 2024

Introduction The effectiveness of Fragment-based drug design (FBDD) for targeting challenging therapeutic targets has been hindered by two factors: the small library size and complexity fragment-to-hit optimization process. DNA-encoded (DEL) technology offers a compelling robust high-throughput selection approach to potentially address these limitations.

Language: Английский

Citations

4
DNA-compatible one-pot synthesis of multi-substituted dihydrofuran via pyridinium ylide-mediated cyclization DOI
Xianfu Fang,

Xiao-Dong Ning,

Yangfeng Li

et al.

Organic & Biomolecular Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Synthesis of chemically diverse heterocyclic scaffolds in DNA-encoded libraries is highly demanded. We herein reported a convenient one-pot multi-component on-DNA synthetic strategy to afford multi-substituted 2,3-dihydrofuran via pyridinium ylide-mediated cyclization. This reaction exhibited modest excellent conversions for broad range DNA-conjugated aldehydes, β-ketonitriles and salts under mild conditions. Furthermore, the compatibility this with DEL construction was verified by enzymatic DNA ligation, PCR amplification mock library synthesis.

Language: Английский

Citations

0
dsDAP: An efficient method for high-abundance DNA-encoded library construction in mammalian cells DOI
Kaili Zhang, Yiping Wang,

S. S. Jiang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 298, P. 140089 - 140089

Published: Jan. 20, 2025

Language: Английский

Citations

0
Discovery of a Potent and in Vivo Anti-inflammatory Efficacious, P2Y14R Antagonist with a Novel Benzisoxazoles Scaffold by DNA-Encoded Chemical Library Technology DOI
Zhiyi Wei,

Bingqian Han,

Longhua Yang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117451 - 117451

Published: Feb. 28, 2025

Language: Английский

Citations

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

Jiale Huang,

Xianfu Fang

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Citations

0
Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors DOI

Ti‐Ti Ying,

Haoqiang Hu,

Xiaowen Wu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117571 - 117571

Published: March 1, 2025

Language: Английский

Citations

0