C-Nucleosides Stabilize RNA by Reducing Nucleophilicity at 2'-OH
Biorxiv : the Preprint Server for Biology
|August 8, 2025
Summary
Carbon-substituted nucleotides like pseudouridine stabilize RNA by reducing strand cleavage rates. This mechanism enhances RNA stability, benefiting both natural RNA and therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- RNA Therapeutics
Background:
- Nucleotides with carbon substitutions for heteroatoms are prevalent in biological and therapeutic RNAs.
- Modified nucleosides, such as pseudouridine and N1-methyl-pseudouridine, are known to increase RNA stability, but the underlying mechanism remains unclear.
Purpose of the Study:
- To investigate the mechanism by which carbon-substituted nucleotides reduce RNA degradation.
- To quantify the impact of carbon substitution on RNA cleavage kinetics.
Main Methods:
- Kinetic analysis of thermal and enzymatic RNA cleavage at the single-bond level.
- Studies on nucleophilic acylation reactions involving modified RNAs and alcohols with varying pKa.
Main Results:
- Carbon substitution significantly reduces the rates of both thermal and enzymatic RNA strand cleavage.
- The reduced cleavage rates are attributed to decreased inductive effects from carbon substitution, leading to higher pKa and lower nucleophilicity.
Conclusions:
- Carbon substitution in nucleotides is a key factor in stabilizing RNA structures.
- Understanding this mechanism provides insights into native RNA modifications and the development of advanced RNA-based therapies.
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