Issue 1, 2021

Modified internucleoside linkages for nuclease-resistant oligonucleotides

Abstract

In the past few years, several drugs derived from nucleic acids have been approved for commercialization and many more are in clinical trials. The sensitivity of these molecules to nuclease digestion in vivo implies the need to exploit resistant non-natural nucleotides. Among all the possible modifications, the one concerning the internucleoside linkage is of particular interest. Indeed minor changes to the natural phosphodiester may result in major modifications of the physico-chemical properties of nucleic acids. As this linkage is a key element of nucleic acids’ chemical structures, its alteration can strongly modulate the plasma stability, binding properties, solubility, cell penetration and ultimately biological activity of nucleic acids. Over the past few decades, many research groups have provided knowledge about non-natural internucleoside linkage properties and participated in building biologically active nucleic acid derivatives. The recent renewing interest in nucleic acids as drugs, demonstrated by the emergence of new antisense, siRNA, aptamer and cyclic dinucleotide molecules, justifies the review of all these studies in order to provide new perspectives in this field. Thus, in this review we aim at providing the reader insights into modified internucleoside linkages that have been described over the years whose impact on annealing properties and resistance to nucleases have been evaluated in order to assess their potential for biological applications. The syntheses of modified nucleotides as well as the protocols developed for their incorporation within oligonucleotides are described. Given the intended biological applications, the modifications described in the literature that have not been tested for their resistance to nucleases are not reported.

Graphical abstract: Modified internucleoside linkages for nuclease-resistant oligonucleotides

Article information

Article type
Review Article
Submitted
27 Jul 2020
Accepted
16 Oct 2020
First published
08 Dec 2020
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2021,2, 94-150

Modified internucleoside linkages for nuclease-resistant oligonucleotides

G. Clavé, M. Reverte, J. Vasseur and M. Smietana, RSC Chem. Biol., 2021, 2, 94 DOI: 10.1039/D0CB00136H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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