Issue 2, 2022

Generation of oligonucleotide conjugates via one-pot diselenide-selenoester ligation–deselenization/alkylation

Abstract

A breadth of strategies are needed to efficiently modify oligonucleotides with peptides or lipids to capitalize on their therapeutic and diagnostic potential, including the modulation of in vivo chemical stability and for applications in cell-targeting and cell-permeability. The chemical linkages typically used in peptide oligonucleotide conjugates (POCs) have limitations in terms of stability and/or ease of synthesis. Herein, we report an efficient method for POC synthesis using a diselenide-selenoester ligation (DSL)-deselenization strategy that rapidly generates a stable amide linkage between the two biomolecules. This conjugation strategy is underpinned by a novel selenide phosphoramidite building block that can be incorporated into an oligonucleotide by solid-phase synthesis to generate diselenide dimer molecules. These can be rapidly ligated with peptide selenoesters and, following in situ deselenization, lead to the efficient generation of POCs. The diselenide within the oligonucleotide also serves as a flexible functionalisation handle that can be leveraged for fluorescent labelling, as well as for alkylation to generate micelles.

Graphical abstract: Generation of oligonucleotide conjugates via one-pot diselenide-selenoester ligation–deselenization/alkylation

Supplementary files

Article information

Article type
Edge Article
Submitted
07 sep 2021
Accepted
17 nov 2021
First published
19 nov 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 410-420

Generation of oligonucleotide conjugates via one-pot diselenide-selenoester ligation–deselenization/alkylation

C. Liczner, C. C. Hanna, R. J. Payne and C. J. Wilds, Chem. Sci., 2022, 13, 410 DOI: 10.1039/D1SC04937B

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