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Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells
Nature Chemistry ( IF 21.8 ) Pub Date : 2020-12-21 , DOI: 10.1038/s41557-020-00605-x
Yiran Huang 1 , Ling Meng 1 , Qigui Nie 2 , Yu Zhou 1 , Langdong Chen 3 , Shilian Yang 2 , Yi Man Eva Fung 1 , Xiaomeng Li 1 , Cen Huang 2 , Yan Cao 3 , Yizhou Li 2, 4 , Xiaoyu Li 1, 5
Affiliation  

Membrane proteins on the cell surface perform a myriad of biological functions; however, ligand discovery for membrane proteins is highly challenging, because a natural cellular environment is often necessary to maintain protein structure and function. DNA-encoded chemical libraries (DELs) have emerged as a powerful technology for ligand discovery, but they are mainly limited to purified proteins. Here we report a method that can specifically label membrane proteins with a DNA tag, and thereby enable target-specific DEL selections against endogenous membrane proteins on live cells without overexpression or any other genetic manipulation. We demonstrate the generality and performance of this method by screening a 30.42-million-compound DEL against the folate receptor, carbonic anhydrase 12 and the epidermal growth factor receptor on live cells, and identify and validate a series of novel ligands for these targets. Given the high therapeutic significance of membrane proteins and their intractability to traditional high-throughput screening approaches, this method has the potential to facilitate membrane-protein-based drug discovery by harnessing the power of DEL.



中文翻译:

针对活细胞上的内源性膜蛋白选择 DNA 编码的化学文库

细胞表面的膜蛋白发挥着无数的生物学功能;然而,膜蛋白的配体发现极具挑战性,因为天然细胞环境通常是维持蛋白质结构和功能所必需的。DNA 编码的化学文库 (DEL) 已成为一种强大的配体发现技术,但它们主要限于纯化的蛋白质。在这里,我们报告了一种可以用 DNA 标签特异性标记膜蛋白的方法,从而能够针对活细胞上的内源性膜蛋白进行目标特异性 DEL 选择,而无需过度表达或任何其他遗传操作。我们通过筛选针对叶酸受体、碳酸酐酶 12 和活细胞上的表皮生长因子受体的 3042 万种化合物 DEL,证明了该方法的普遍性和性能,并识别和验证这些目标的一系列新配体。鉴于膜蛋白的高治疗意义及其对传统高通量筛选方法的难处理性,该方法有可能通过利用 DEL 的力量促进基于膜蛋白的药物发现。

更新日期:2020-12-21
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