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

Autor: Zhou Y; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China.; Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Hong Kong SAR, China., Shen W; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Gao Y; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Peng J; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Li Q; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Wei X; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Liu S; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Lam FS; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China., Mayol-Llinàs J; Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Hong Kong SAR, China., Zhao G; Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China., Li G; Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China., Li Y; Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China., Sun H; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China. hsun@hku.hk., Cao Y; School of Pharmacy, Naval Medical University, Shanghai, China. caoyan@smmu.edu.cn., Li X; Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, China. xiaoyuli@hku.hk.; Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Hong Kong SAR, China. xiaoyuli@hku.hk.
Jazyk: angličtina
Zdroj: Nature chemistry [Nat Chem] 2024 Apr; Vol. 16 (4), pp. 543-555. Date of Electronic Publication: 2024 Feb 07.
DOI: 10.1038/s41557-024-01442-y
Abstrakt: DNA-encoded chemical libraries (DELs) have become a powerful technology platform in drug discovery. Dual-pharmacophore DELs display two sets of small molecules at the termini of DNA duplexes, thereby enabling the identification of synergistic binders against biological targets, and have been successfully applied in fragment-based ligand discovery and affinity maturation of known ligands. However, dual-pharmacophore DELs identify separate binders that require subsequent linking to obtain the full ligands, which is often challenging. Here we report a protein-templated DEL selection approach that can identify full ligand/inhibitor structures from DNA-encoded dynamic libraries (DEDLs) without the need for subsequent fragment linking. Our approach is based on dynamic DNA hybridization and target-templated in situ ligand synthesis, and it incorporates and encodes the linker structures in the library, along with the building blocks, to be sampled by the target protein. To demonstrate the performance of this method, 4.35-million- and 3.00-million-member DEDLs with different library architectures were prepared, and hit selection was achieved against four therapeutically relevant target proteins.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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