Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification
Full article
| Journal |
Molecules
ISSN: 1420-3049
|
| Output data |
Year: 2024,
Volume: 29,
Number: 4,
Article number
: 786,
Pages count
:
DOI:
10.3390/molecules29040786
|
| Tags |
siRNA; chemical modifications; cholesterol conjugate; nuclease resistance; duration of silencing; MDR1 gene |
| Authors |
Chernikov Ivan V.
1
,
Ponomareva Ul’yana A.
1
,
Meschaninova Mariya I.
1
,
Bachkova Irina K.
2,1
,
Vlassov Valentin V.
1
,
Zenkova Marina A.
1
,
Chernolovskaya Elena L.
1
|
| Affiliations |
| 1 |
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Academic Lavrentiev Avenue 8, 630090 Novosibirsk, Russia
|
| 2 |
Faculty of Natural Sciences, Novosibirsk State University, Pirogova Str. 1, 630090 Novosibirsk, Russia
|
|
Funding (2)
|
1
|
МИНИСТЕРСТВО НАУКИ И ВЫСШЕГО ОБРАЗОВАНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ
|
ПФНИ РФ (2021-2030) 0245-2021-0004
|
|
2
|
Russian Science Foundation
|
РНФ №19-1400251 (продление)
|
Cholesterol siRNA conjugates attract attention because they allow the delivery of siRNA into cells without the use of transfection agents. In this study, we compared the efficacy and duration of silencing induced by cholesterol conjugates of selectively and totally modified siRNAs and their heteroduplexes of the same sequence and explored the impact of linker length between the 3′ end of the sense strand of siRNA and cholesterol on the silencing activity of “light” and “heavy” modified siRNAs. All 3′-cholesterol conjugates were equally active under transfection, but the conjugate with a C3 linker was less active than those with longer linkers (C8 and C15) in a carrier-free mode. At the same time, they were significantly inferior in activity to the 5′-cholesterol conjugate. Shortening the sense strand carrying cholesterol by two nucleotides from the 3′-end did not have a significant effect on the activity of the conjugate. Replacing the antisense strand or both strands with fully modified ones had a significant effect on silencing as well as improving the duration in transfection-mediated and carrier-free modes. A significant 78% suppression of MDR1 gene expression in KB-8-5 xenograft tumors developed in mice promises an advantage from the use of fully modified siRNA cholesterol conjugates in combination chemotherapy.