Multivalent RNA-Cleaving Agents on a Cubic Octameric Silsesquioxane Core

Area of Science:

• Medicinal Chemistry
• Materials Science
• Biochemistry

Background:

• Selective RNA cleavage is crucial for developing new therapeutic strategies.
• Designing efficient and specific RNA-cleaving agents remains a challenge.
• Cubic octameric silsesquioxane (COSS) cores offer a platform for multivalent catalyst synthesis.

Purpose of the Study:

• To synthesize and evaluate multivalent RNA-cleaving agents based on a COSS core.
• To compare the catalytic efficiencies of metal-organic and organocatalysts.
• To assess the site-specificity and potential therapeutic applications of these agents.

Main Methods:

• Synthesis of COSS-based catalysts featuring 1,5,9-triazacyclododecane (TACD) or guanidine groups.
• Evaluation of catalytic activity using hexaribonucleotide models and a HER2 mRNA model sequence.
• Comparison of catalyst performance in the presence and absence of metal ions (Zn²⁺, Cu²⁺, Pd²⁺).
• Determination of RNA cleavage sites and correlation with catalyst concentration.

Main Results:

• COSS-lysine(N₃)-TACD-Zn²⁺ ₈ showed selectivity for uracil bases in hexaribonucleotides.
• An organocatalyst (COSS-lysine(N₃)-arginine) outperformed a metal-organic catalyst in HER2 mRNA cleavage efficiency.
• Organocatalysts (COSS-lysine(N₃)-arginine and COSS-lysine(N₃)-guanidine) demonstrated clear site-specificity.
• Catalyst concentration correlated with reaction rates.

Conclusions:

• Novel COSS-based RNA-cleaving agents were successfully synthesized and characterized.
• Organocatalysts exhibit superior site-specificity compared to metal-organic counterparts for HER2 mRNA cleavage.
• These findings highlight the potential of COSS-based organocatalysts for targeted RNA therapeutics.