Chernikov, I.V.; Ponomareva, U.A.; Meschaninova, M.I.; Bachkova, I.K.; Vlassov, V.V.; Zenkova, M.A.; Chernolovskaya, E.L. Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification. Molecules2024, 29, 786.
Chernikov, I.V.; Ponomareva, U.A.; Meschaninova, M.I.; Bachkova, I.K.; Vlassov, V.V.; Zenkova, M.A.; Chernolovskaya, E.L. Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification. Molecules 2024, 29, 786.
Chernikov, I.V.; Ponomareva, U.A.; Meschaninova, M.I.; Bachkova, I.K.; Vlassov, V.V.; Zenkova, M.A.; Chernolovskaya, E.L. Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification. Molecules2024, 29, 786.
Chernikov, I.V.; Ponomareva, U.A.; Meschaninova, M.I.; Bachkova, I.K.; Vlassov, V.V.; Zenkova, M.A.; Chernolovskaya, E.L. Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification. Molecules 2024, 29, 786.
Abstract
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 are significantly inferior in activity to the 5'-cholesterol conjugate. Shortening the sense strand carrying cholesterol by 2 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 has 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.
Keywords
siRNA; chemical modifications; cholesterol conjugate; nuclease resistance; duration of silencing; MDR1 gene
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
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.
,
,
,
