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

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

Журнал

Pharmaceutics
ISSN: 1999-4923

Вых. Данные

Год: 2023, Том: 15, Номер: 12, Номер статьи : 2779, Страниц : DOI: 10.3390/pharmaceutics15122779

Ключевые слова

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

Авторы

Bauer I.A. ^1,2 , Ilina E.S. ^1,2 , Zharkov T.D. ¹ , Grigoryeva E.V. ¹ , Chinak O.A. ¹ , Kupryushkin M.S. ¹ , Golyshev V.M. ¹ , Mitin D.E. ¹ , Chubarov A.S. ^1,2 , Khodyreva S.N. ¹ , Dmitrienko E.V. ^1,2

Организации

1	Institute of Chemical Biology and Fundamental Medicine SB RAS, 630090 Novosibirsk, Russia
2	Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia

Информация о финансировании (1)

МИНИСТЕРСТВО НАУКИ И ВЫСШЕГО ОБРАЗОВАНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ

ПФНИ РФ (2021-2030) 0245-2021-0007

Lipophilic oligonucleotide derivatives are a potent approach to the intracellular delivery of nucleic acids. The binding of these derivatives to serum albumin is a 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.

Bauer I.A. , Ilina E.S. , Zharkov T.D. , Grigoryeva E.V. , Chinak O.A. , Kupryushkin M.S. , Golyshev V.M. , Mitin D.E. , Chubarov A.S. , Khodyreva S.N. , Dmitrienko E.V.
Self-Penetrating Oligonucleotide Derivatives: Features of Self-Assembly and Interactions with Serum and Intracellular Proteins
Pharmaceutics. 2023. Т.15. №12. 2779 . DOI: 10.3390/pharmaceutics15122779 WOS Scopus PMID OpenAlex

Опубликована в печати:

13 дек. 2023 г.

Web of science:	WOS:001130911800001
Scopus:	2-s2.0-85180730264
PMID (PubMed):	37834092
OpenAlex:	W4389816394

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