香港大学李笑宇团队报道了通过选择DNA编码的动态库发现蛋白质模板配体。相关研究成果发表在2024年2月7日出版的《自然—化学》。

DNA编码化学库（DELs）已成为药物发现的强大技术平台。双药效团DELs在DNA双链体的末端显示两组小分子，从而能够识别针对生物靶标的协同结合物，并已成功应用于基于片段的配体发现和已知配体的亲和力成熟。然而，双药效团DELs识别出需要随后连接以获得完整配体的单独粘合剂，这通常是具有挑战性的。

该文中，研究人员报道了一种蛋白质模板DELs选择方法，该方法可以从DNA编码的动态库（DEDLs）中鉴定完整的配体/抑制剂结构，而不需要随后的片段连接。该方法基于动态DNA杂交和靶模板原位配体合成，并结合并编码库中的连接体结构，以及将由靶蛋白采样的构建块。为了证明该方法的性能，制备了435万和300万个具有不同库结构的成员DEDLs，并实现了对四种治疗相关靶蛋白的命中选择。

附：英文原文

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

Author: Zhou, Yu, Shen, Wenyin, Gao, Ying, Peng, Jianzhao, Li, Qingrong, Wei, Xueying, Liu, Shihao, Lam, Fong Sang, Mayol-Llins, Joan, Zhao, Guixian, Li, Gang, Li, Yizhou, Sun, Hongzhe, Cao, Yan, Li, Xiaoyu

Issue&Volume: 2024-02-07

Abstract: 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.

DOI: 10.1038/s41557-024-01442-y

Source: https://www.nature.com/articles/s41557-024-01442-y