瑞士苏黎士联邦理工学院Dario Neri团队提出，立体定向和区域定向DNA编码的化学文库可以有效地用于肿瘤靶向治疗。 相关研究成果发表在2021年4月8日出版的国际学术期刊《自然-化学》。

利用可扩增的DNA标记对化合物进行编码，有利于蛋白质小分子配体的发现。

为了研究立体化学和区域化学对配体发现的影响，研究人员合成了670752个基于2-叠氮基-3-碘苯基丙酸的衍生物的DNA编码文库。该文库针对多种蛋白质进行筛选，并获得了特异性配体。

对一组具有药物相关性的蛋白质靶点所获得的选择指纹图谱清楚地显示了邻位、间位或对位异构体的优先富集，在没有DNA的情况下通过亲和力测量得到了实验验证。所发现的配体包括新的选择性酶抑制剂和肿瘤相关抗原的结合物，这使得条件嵌合抗原受体T细胞活化和肿瘤靶向成为可能。

附：英文原文

Title: Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications

Author: Nicholas Favalli, Gabriele Bassi, Christian Pellegrino, Jacopo Millul, Roberto De Luca, Samuele Cazzamalli, Su Yang, Anika Trenner, Nour L. Mozaffari, Renier Myburgh, Mustafa Moroglu, Stuart J. Conway, Alessandro A. Sartori, Markus G. Manz, Richard A. Lerner, Peter K. Vogt, Jrg Scheuermann, Dario Neri

Issue&Volume: 2021-04-08

Abstract: The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.

DOI: 10.1038/s41557-021-00660-y

Source: https://www.nature.com/articles/s41557-021-00660-y