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Oligonucleotide Phosphorothioates Enter Cells by Thiol‐Mediated Uptake
Author(s) -
Laurent Quentin,
Martinent Rémi,
Moreau Dimitri,
Winssinger Nicolas,
Sakai Naomi,
Matile Stefan
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202107327
Subject(s) - oligonucleotide , cytosol , thiol , endosome , chemistry , dna , covalent bond , mechanism of action , combinatorial chemistry , sulfur , biochemistry , rna , biophysics , cell , in vitro , gene , biology , enzyme , organic chemistry
Abstract 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.