Oligonucleotide Phosphorothioates Enter Cells by Thiol-Mediated Uptake,Angewandte Chemie International Edition

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Oligonucleotide Phosphorothioates Enter Cells by Thiol-Mediated Uptake
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-06-26 , DOI: 10.1002/anie.202107327
Quentin Laurent ₁ , Rémi Martinent ₁ , Dimitri Moreau ₁ , Nicolas Winssinger ₁ , Naomi Sakai ₁ , Stefan Matile ₁

Affiliation

Oligonucleotide phosphorothioates (OPS) are DNA or RNA mimics where one phosphate oxygen is replaced by a sulfur atom. They have been shown to enter mammalian cells much more efficiently than non-modified DNA. Thus, solving one of the key challenges with oligonucleotide technology, OPS became very useful in practice, with several FDA-approved drugs on the market or in late clinical trials. However, the mechanism accounting for this facile cellular uptake is unknown. Here, we show that OPS enter cells by thiol-mediated uptake. The transient adaptive network produced by dynamic covalent pseudo-disulfide exchange is characterized in action. Inhibitors with nanomolar efficiency are provided, together with activators that reduce endosomal capture for efficient delivery of OPS into the cytosol, the site of action.

中文翻译：

寡核苷酸硫代磷酸酯通过硫醇介导的摄取进入细胞

寡核苷酸硫代磷酸酯 (OPS) 是 DNA 或 RNA 模拟物，其中一个磷酸氧被硫原子取代。研究表明，它们比未经修饰的 DNA 更能有效地进入哺乳动物细胞。因此，通过解决寡核苷酸技术的关键挑战之一，OPS 在实践中变得非常有用，有几种 FDA 批准的药物已上市或处于后期临床试验中。然而，这种容易的细胞摄取的机制尚不清楚。在这里，我们证明 OPS 通过硫醇介导的摄取进入细胞。动态共价假二硫键交换产生的瞬态自适应网络的特征在于其作用。提供具有纳摩尔效率的抑制剂，以及减少内体捕获的激活剂，以将 OPS 有效递送到细胞质（作用位点）中。

更新日期：2021-08-17

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