Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

Timofey D. Zharkov
ORCID logo ,
Oleg V. Markov
,
Sergey A. Zhukov
ORCID logo ,
Svetlana N. Khodyreva
,
Maxim S. Kupryushkin
* ORCID logo
Version 1 : Received: 9 December 2023 / Approved: 11 December 2023 / Online: 11 December 2023 (07:48:01 CET)

A peer-reviewed article of this Preprint also exists.

Zharkov, T.D.; Markov, O.V.; Zhukov, S.A.; Khodyreva, S.N.; Kupryushkin, M.S. Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides. Molecules 2024, 29, 452. Zharkov, T.D.; Markov, O.V.; Zhukov, S.A.; Khodyreva, S.N.; Kupryushkin, M.S. Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides. Molecules 2024, 29, 452.

Abstract

Numerous types of oligonucleotide modifications have been developed since automated synthesis of DNA/RNA became a common instrument in the creation of synthetic oligonucleotides. Despite the growing number of types of oligonucleotide modifications under development, only a few of them, and moreover, their combinations have been studied wide enough in terms of their in-fluence on the properties of corresponding NA constructions. In the present study, a number of oligonucleotides with combinations of 3′ end lipophilic (single cholesteryl or pair of dodecyl residues) and phosphate backbone modifications were synthesized. The influence of the combi-nation of used lipophilic groups with phosphate modifications of various nature and different position on the efficiency of cell penetration was evaluated. Obtained results indicate that even a couple of phosphate modifications are able to affect a set of oligonucleotide properties in a complex manner and can remarkably change cellular uptake. These data clearly show that the strategy of using different patterns of modification combinations has great potential for the ra-tional design of oligonucleotide structures with desired predefined properties.

Keywords

lipophilic oligonucleotides; phosphate modifications; phosphoryl guanidine; triazinyl phosphoramidate; conjugates; delivery

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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