A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging†,Chemical Science

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A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging†
Chemical Science ( IF 7.6 ) Pub Date : 2018-04-06 00:00:00 , DOI: 10.1039/c8sc00256h
Benjamin J. Stenton _{1,

2,

3,

4} , Bruno L. Oliveira _{1,

2,

3,

4} , Maria J. Matos _{1,

2,

3,

4} , Laura Sinatra _{1,

2,

3,

4} , Gonçalo J. L. Bernardes _{1,

2,

3,

4,

5}

Affiliation

We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated for the construction of an anti-HER2 nanobody–drug conjugate. Targeted delivery of the nanobody drug conjugate showed effective cell killing in HER2+ cells upon palladium-mediated decaging.

中文翻译：

用于靶向生物正交药物降解的硫醚导向的钯可裂解连接子†

我们描述了双功能连接器的开发，该连接器同时允许位点特异性蛋白质修饰和钯介导的生物正交降解。这是通过炔丙基氨基甲酸酯连接基中的硫醚结合基序和易于获得的钯配合物实现的。我们通过在癌细胞中从聚乙二醇化的阿霉素前药中控制药物的释放证明了该反应的效率。该接头可轻松安装到带有半胱氨酸的蛋白质中，我们已证明该蛋白质可用于构建抗HER2纳米抗体-药物偶联物。纳米抗体偶联物的靶向递送显示出在钯介导的衰老后HER2 +细胞中的有效细胞杀伤。

更新日期：2018-04-06

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