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Caprin‐1 Promotes Cellular Uptake of Nucleic Acids with Backbone and Sequence Discrimination
Helvetica Chimica Acta ( IF 1.5 ) Pub Date : 2019-12-23 , DOI: 10.1002/hlca.201900255
Valentina Galli 1 , Kalyan K. Sadhu 1 , Daniela Masi 1 , Jacques Saarbach 1 , Aurélien Roux 1 , Nicolas Winssinger 1
Affiliation  

The cellular delivery of oligonucleotides has been a major obstacle in the development of therapeutic antisense agents. PNAs (Peptide Nucleic Acid) are unique in providing a modular peptidic backbone that is amenable to structural and charge modulation. While cationic PNAs have been shown to be taken up by cells more efficiently than neutral PNAs, the generality of uptake across different nucleobase sequences has never been tested. Herein, we quantified the relative uptake of PNAs across a library of 10 000 sequences for two different PNA backbones (cationic and neutral) and identified sequences with high uptake and low uptake. We used the high uptake sequence as a bait for target identification, leading to the discovery that a protein, caprin‐1, binds to PNA with backbone and sequence discrimination. We further showed that purified caprin‐1 added to cell cultures enhanced the cellular uptake of PNA as well as DNA and RNA.

中文翻译:

Caprin-1通过骨干和序列区分促进核酸对细胞的摄取。

寡核苷酸的细胞递送一直是治疗性反义剂开发中的主要障碍。PNA(肽核酸)在提供可适应结构和电荷调节的模块化肽主链方面具有独特性。尽管已显示阳离子PNA比中性PNA更有效地被细胞吸收,但从未测试过跨不同核碱基序列的摄取普遍性。在本文中,我们对两个不同的PNA主链(阳离子和中性)的10000个序列的库中的PNA的相对摄取进行了定量,并确定了高摄取和低摄取的序列。我们使用高摄取序列作为靶标识别的诱饵,从而发现了一种蛋白质,caprin-1与骨架和序列区分的PNA结合。
更新日期:2019-12-23
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