DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery

Zhou, Yu1,2; Li, Chen1; Peng, Jianzhao2,3; Xie, Lianxu4; Men, Ling2; Li, Qingrong2,3; Zhang, Jianfu2; Li, Xiang David2; Li, Xin2; Huang, Xuhui4; Li, Xiaoyu2

2018-11-21

10.1021/jacs.8b09277

Journal of the American Chemical Society   影响因子和分区

0002-7863

Dynamic combinatorial library (DCL) has emerged as an efficient tool for ligand discovery and become an important discovery modality in biomedical research. However, the applications of DCLs have been significantly hampered by low library diversity and limited analytical methods capable of processing large libraries. Here, we report a strategy that has addressed this limitation and can select cooperatively binding small-molecule pairs from large-scale dynamic libraries. Our approach is based on DNA-mediated dynamic hybridization, DNA-encoding, and a photo-cross linking-based decoding scheme. To demonstrate the generality and performance of this approach, a 10 000-member DNA-encoded dynamic library has been prepared and selected against six protein targets. Specific binders have been identified for each target, and we have validated the biological activities of selected ligands for the targets that are implicated in important cellular functions including protein deacetylation and sumoylation. Notably, a series of novel and selective sirtuin-3 inhibitors have been developed. Our study has circumvented a major obstacle in DCL and may provide a broadly applicable method for ligand discovery against biological targets.

SCI ; EI ; IC

英语

NI期刊

其他

[201601159018]

Chemistry

Chemistry, Multidisciplinary

WOS:000451496800044

AMER CHEMICAL SOC

20184806143230

Acetylation ; Libraries ; Ligands ; Proteins

Biological Materials and Tissue Engineering:461.2 ; Physical Chemistry:801.4 ; Chemical Reactions:802.2 ; Organic Compounds:804.1 ; Libraries:903.4.1

Web of Science

1.Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Key Lab Chem Genom, 2199 Lishui Rd West, Shenzhen 518055, Peoples R China
2.Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
3.Southern Univ Sci & Technol, Dept Chem, 1088 Xueyuan Rd, Shenzhen 518055, Peoples R China
4.Hong Kong Univ Sci & Technol, Dept Chem, Kowloon, Hong Kong, Peoples R China

Zhou, Yu,Li, Chen,Peng, Jianzhao,et al. DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery[J]. Journal of the American Chemical Society,2018,140(46):15859-15867.

Zhou, Yu.,Li, Chen.,Peng, Jianzhao.,Xie, Lianxu.,Men, Ling.,...&Li, Xiaoyu.(2018).DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery.Journal of the American Chemical Society,140(46),15859-15867.

Zhou, Yu,et al."DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery".Journal of the American Chemical Society 140.46(2018):15859-15867.