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Related Experiment Video

Updated: Nov 1, 2025

Chemical Triphosphorylation of Oligonucleotides

Chemical Triphosphorylation of Oligonucleotides

Published on: June 2, 2022

Oligonucleotide Phosphorothioates Enter Cells by Thiol-Mediated Uptake.

Quentin Laurent¹, Rémi Martinent¹, Dimitri Moreau¹

¹School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland.

Angewandte Chemie (International Ed. in English)

|June 26, 2021

Summary

Oligonucleotide phosphorothioates (OPS) enter cells via thiol-mediated uptake, a mechanism involving dynamic covalent bonds. Researchers developed inhibitors and activators to control this process for improved drug delivery.

Keywords:

cellular uptake dynamic covalent chemistry oligonucleotides phosphorothioates

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Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

Area of Science:

Biochemistry
Molecular Biology
Drug Delivery

Background:

Oligonucleotide phosphorothioates (OPS) are DNA/RNA mimics with enhanced cellular entry compared to unmodified DNA.
OPS have significant therapeutic potential, evidenced by FDA-approved drugs and late-stage clinical trials.
The cellular uptake mechanism for OPS remains largely unknown, hindering further development.

Purpose of the Study:

To elucidate the mechanism of cellular uptake for oligonucleotide phosphorothioates (OPS).
To identify molecular components and pathways involved in OPS cellular entry.
To develop strategies for enhancing OPS delivery into the cytosol.

Main Methods:

Characterization of the transient adaptive network formed by dynamic covalent pseudo-disulfide exchange during OPS uptake.
Utilizing inhibitors and activators to modulate OPS cellular entry.
Investigating endosomal escape mechanisms for cytosolic delivery.

Main Results:

Demonstrated that OPS cellular uptake is mediated by thiols.
Identified a dynamic covalent pseudo-disulfide exchange mechanism governing OPS entry.
Developed potent inhibitors (nanomolar efficiency) and activators to control OPS uptake and cytosolic delivery.

Conclusions:

Thiol-mediated uptake is the primary mechanism for cellular entry of oligonucleotide phosphorothioates (OPS).
Dynamic covalent chemistry plays a crucial role in the cellular internalization of OPS.
Targeted inhibitors and activators can significantly enhance the efficiency of OPS delivery into the cytosol for therapeutic applications.