Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins

Irina Bauer
ORCID logo ,
Ekaterina Ilina
,
Timofey Zharkov
ORCID logo ,
Evgeniya Grigorieva
,
Olga Chinak
ORCID logo ,
Maxim Kupryushkin
,
Victor Golyshev
ORCID logo ,
Dmitry Mitin
,
Alexey Chubarov
* ORCID logo ,
Svetlana Khodyreva
,
Elena Dmitrienko
* ORCID logo
Version 1 : Received: 11 December 2023 / Approved: 12 December 2023 / Online: 12 December 2023 (13:53:44 CET)

A peer-reviewed article of this Preprint also exists.

Bauer, I.; Ilina, E.; Zharkov, T.; Grigorieva, E.; Chinak, O.; Kupryushkin, M.; Golyshev, V.; Mitin, D.; Chubarov, A.; Khodyreva, S.; Dmitrienko, E. Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins. Pharmaceutics 2023, 15, 2779. Bauer, I.; Ilina, E.; Zharkov, T.; Grigorieva, E.; Chinak, O.; Kupryushkin, M.; Golyshev, V.; Mitin, D.; Chubarov, A.; Khodyreva, S.; Dmitrienko, E. Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins. Pharmaceutics 2023, 15, 2779.

Abstract

Lipophilic oligonucleotide derivatives are a potent approach to the intracellular delivery of nucleic acids. The binding of these derivatives to serum albumin is a major determinant of their fate in the body, as its structure contains several sites of high affinity for hydrophobic compounds. This study focuses on the features of self-association and non-covalent interactions with human serum albumin of novel self-penetrating oligonucleotide derivatives. The study revealed that the introduction of a triazinyl phosphoramidate modification bearing two dodecyl groups at the 3' end region of the oligonucleotide sequence has a negligible effect on its affinity for the complementary sequence. Dynamic light scattering verified that the amphiphilic oligonucleotides under study can self-assemble into micelle-like particles ranging from 8 to 15 nm in size. The oligonucleotides with dodecyl groups form stable complexes with human serum albumin with a dissociation constant of approximately 10-6 M. The oligonucleotide micelles are simultaneously destroyed upon binding to albumin. Using an electrophoretic mobility shift assay and affinity modification, we examined the ability of DNA duplexes containing triazinyl phosphoramidate oligonucleotides to interact with Ku antigen and PARP1, as well as the mutual influence of PARP1 and albumin or Ku antigen and albumin upon interaction with DNA duplexes. These findings, together with the capability of dodecyl-containing derivatives to effectively penetrate different cells, such as HEK293 and T98G, indicate that the oligonucleotides under study can be considered as a platform for the development of therapeutic preparations with a target effect.

Keywords

triazinyl phosphoramidate; amphiphilic oligonucleotides; self-assembly; human serum albumin; Ku antigen; PARP1; protein-oligonucleotide complexes

Subject

Biology and Life Sciences, Life Sciences

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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