Issue 42, 2023

Rational optimization of siRNA to ensure strand bias in the interaction with the RNA-induced silencing complex

Abstract

To ensure specificity of small interfering RNAs (siRNAs), the antisense strand must be selected by the RNA-induced silencing complex (RISC). We have previously demonstrated that a 5′-morpholino-modified nucleotide at the 5′-end of the sense strand inhibits its interaction with RISC ensuring selection of the desired antisense strand. To improve this antagonizing binding property even further, a new set of morpholino-based analogues, Mo2 and Mo3, and a piperidine analogue, Pip, were designed based on the known structure of Argonaute2, the slicer enzyme component of RISC. Sense strands of siRNAs were modified with these new analogues, and the siRNAs were evaluated in vitro and in mice for RNAi activity. Our data demonstrated that Mo2 is the best RISC inhibitor among the modifications tested and that it effectively mitigates sense strand-based off-target activity of siRNA.

Graphical abstract: Rational optimization of siRNA to ensure strand bias in the interaction with the RNA-induced silencing complex

Supplementary files

Article information

Article type
Communication
Submitted
10 Kul 2023
Accepted
21 Kul 2023
First published
10 Dzi 2023

Chem. Commun., 2023,59, 6347-6350

Rational optimization of siRNA to ensure strand bias in the interaction with the RNA-induced silencing complex

D. Datta, C. S. Theile, K. Wassarman, J. Qin, T. Racie, K. Schmidt, Y. Jiang, R. Sigel, M. M. Janas, M. Egli and M. Manoharan, Chem. Commun., 2023, 59, 6347 DOI: 10.1039/D3CC01143G

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements