Multivalent RNA-Cleaving Agents on a Cubic Octameric Silsesquioxane Core

Selective RNA cleavage could provide versatile options in therapeutic applications. In this study, multivalent RNA-cleaving agents, featuring 1,5,9-triazacyclododecane or guanidine groups as catalytic centers, were synthesized on a cubic octameric silsesquioxane (COSS) core. Their catalytic efficiencies were first evaluated and compared in the presence and absence of metal ions Zn²⁺, Cu²⁺, and Pd²⁺ using hexaribonucleotide models. COSS-lysine(N₃)-TACD-Zn²⁺ ₈ exhibited base moiety selectivity for uracil bases, resulting in half-lives of 2-11 h for the cleavage of the uracil-containing hexaribonucleotides. Then, the cleavage of a biologically relevant HER2 mRNA model sequence was studied with the most effective catalysts. Surprisingly, an organocatalyst (COSS-lysine(N₃)-arginine) outperformed a metal-organic catalyst (COSS-lysine(N₃)-TACD-Zn²⁺ ₈) in catalytic efficiency, the half-lives being 14 and 31 h, respectively. In addition, the cleavage sites of the HER2 mRNA model were determined. While the COSS-lysine(N₃)-TACD-Zn²⁺ ₈ produced high background cleavage, the organic catalysts COSS-lysine(N₃)-arginine and COSS-lysine(N₃)-guanidine exhibited clear site-specificity in the HER2 mRNA cleavage. Additionally, a correlation between the reaction rates and the amount of the catalysts was verified by varying the catalyst concentrations. Fast reaction rates and site-specificity of the cleavage indicate good potential for further development of these cleaving agents.