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

• Published in: Journal of the American Chemical Society Vol. 140; no. 46; pp. 15859 - 15867
• Main Authors: Zhou, Yu, Li, Chen, Peng, Jianzhao, Xie, Liangxu, Meng, Ling, Li, Qingrong, Zhang, Jianfu, Li, Xiang David, Li, Xin, Huang, Xuhui, Li, Xiaoyu
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.11.2018; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; IN-VITRO; DESIGN; IMPACT; COMBINATORIAL CHEMISTRY; BINDING PROTEINS; INHIBITORS; SELECTION; IDENTIFICATION; SMALL-MOLECULE DISCOVERY; SUMOYLATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.8b09277

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.