连接器
肟
泛素连接酶
蛋白质水解
化学
嵌合体(遗传学)
组合化学
药物发现
泛素
醛
计算生物学
立体化学
生物化学
生物物理学
纳米技术
细胞生物学
计算机科学
生物
材料科学
催化作用
酶
基因
操作系统
作者
Weijun Gui,Thomas Kodadek
出处
期刊:ChemBioChem
[Wiley]
日期:2022-07-28
卷期号:23 (18)
被引量:4
标识
DOI:10.1002/cbic.202200275
摘要
Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker connecting the E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands, which therefore requires tedious optimization. The creation of "split PROTACs" from E3 Ubl and TP ligands modified with residues suitable for them to couple when simply mixed together would allow various combinations to be assessed in a combinatorial fashion, thus greatly easing the workload relative to a one-by-one synthesis of many different PROTACs (proteolysis targeting chimeras). We explore oxime chemistry here for this purpose. We show that PROTAC assembly occurs efficiently when the components are mixed at a high concentration, then added to cells. However, in situ coupling of the TP and E3 Ubl ligands is inefficient when these units are added to cells at lower concentrations.
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