State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Bioconjug Chem. 2022 Oct 19;33(10):1818-1824. doi: 10.1021/acs.bioconjchem.2c00421. Epub 2022 Oct 5.
The DNA-encoded compound library (DEL) technology has accelerated the target hits discovery in new drug development. While affinity-based DEL selection can distinguish high-affinity ligands, moderate-affinity ligands are also potential drug candidates with further modifications. Herein, we designed a photo-cross-linking selection method for DELs with double-stranded DNA (dsDELs) to screen moderate-affinity ligands. We constructed two photo-cross-linking libraries with linkers of different lengths that connect a diazirine group to the DNA encoded compound. The diazirine group can be activated by UV irradiation and thus bond with the target protein in a reachable distance. In the model selection, the feasibility of the photo-cross-linking screening system was verified by qPCR and NGS technology. Both high-affinity and moderate-affinity ligands were successfully selected from the libraries.
DNA 编码化合物库 (DEL) 技术加速了新药开发中的靶标发现。虽然基于亲和力的 DEL 选择可以区分高亲和力配体，但中等亲和力的配体也是具有进一步修饰潜力的潜在药物候选物。在此，我们设计了一种带有双链 DNA (dsDEL) 的用于 DEL 的光交联选择方法，以筛选中等亲和力的配体。我们构建了两个带有不同长度接头的光交联文库，将叠氮基团连接到 DNA 编码化合物上。叠氮基团可以通过紫外线照射激活，从而与可及距离内的靶蛋白结合。在模型选择中，通过 qPCR 和 NGS 技术验证了光交联筛选系统的可行性。文库中成功地选择了高亲和力和中等亲和力的配体。
