Desaulniers, Jean-Paul; Hammill, Matthew L; Giorgees, Ifrodet; Chiu, Virginia Wing-Nam; Pendergraff, Hannah; Aguti, Sara; Voutila, Jon; ... Koch, Troels; + view all Desaulniers, Jean-Paul; Hammill, Matthew L; Giorgees, Ifrodet; Chiu, Virginia Wing-Nam; Pendergraff, Hannah; Aguti, Sara; Voutila, Jon; Hansen, Henrik; Habib, Nagy; Lomonosova, Yulia; Koch, Troels; - view fewer (2025) Exploring Chemically Modified Short Activating RNAs to Increase Stability against Nucleases and Enhance Gene Activation. Journal of Medicinal Chemistry , 68 (21) pp. 22650-22664. 10.1021/acs.jmedchem.5c01648.

Text Desaulniers_Koch_Manuscript_JMC_no_highlights.pdf - Accepted Version Access restricted to UCL open access staff until 24 October 2026. Download (7MB)

Abstract

Short activating RNAs (saRNAs) are short duplex RNAs that activate genes in the nucleus of the cell. This induces gene activation, or RNA activation (RNAa), which upregulates gene expression. This activation is in direct contrast to short interfering RNAs (siRNAs), which downregulate gene expression through the activation of Argonaute 2 within the RNA-induced silencing complex (RISC). siRNA chemical modifications such as 2'-O-Me, 2'-F, locked nucleic acids (LNA), unlocked nucleic acids (UNA), and backbone modifications such as phosphorothioate (PS) have been well documented and studied. In this study, a library of chemically modified saRNAs was synthesized and evaluated for their ability to activate gene expression. We have identified that a thermally destabilizing abasic carbon-based linker within the central region of the sense strand, in conjunction with an affinity-enhancing nucleoside, LNA, on the antisense strand, offers optimal duplex melting temperature, nuclease stability, and enhanced gene activation.

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