RNA 2'-OH modification with stable reagents enabled by nucleophilic catalysis.
Eric T Kool1, Sumon Pratihar1, Pavitra S Thacker1
1Department of Chemistry, Stanford University Stanford California USA kool@stanford.edu.
RSC Advances
|September 29, 2025
Summary
Researchers developed stable electrophilic reagents for RNA modification, overcoming challenges with reactive species. These new reagents, like aryl esters, offer improved stability and selectivity for RNA 2-hydroxyl modifications.
Area of Science:
- Biochemistry
- Organic Chemistry
- Molecular Biology
Background:
- Traditional RNA modification at the 2'-OH group requires highly reactive acylating agents.
- These reactive agents have short half-lives in water, complicating purification and limiting storage.
- This necessitates the development of more stable and manageable reagents for RNA chemistry.
Purpose of the Study:
- To investigate the use of stable electrophilic reagents for RNA modification.
- To explore the application of nucleophilic catalysis in promoting reactions with these stable reagents.
- To expand the range of functional chemical structures (chemotypes) capable of reacting with RNA.
Main Methods:
- Utilized stable electrophilic reagents in conjunction with nucleophilic catalysis.
- Tested various previously unreported electrophiles for their reactivity with RNA.
- Investigated the reaction kinetics and stability of aryl esters in aqueous solutions.
Main Results:
- Demonstrated that multiple stable electrophiles can react with RNA in high yields under catalytic conditions.
- Showcased aryl esters as effective acylating agents, reacting within one hour.
- Confirmed the long-term stability of aryl esters (months) in pure water.
- Identified new classes of RNA-reactive reagents with enhanced stability and selectivity.
Conclusions:
- Developed novel, stable electrophilic reagents for RNA modification, overcoming limitations of previous methods.
- Aryl esters represent a promising class of reagents for efficient and selective RNA 2'-OH acylation.
- The findings broaden the scope of chemical strategies for RNA functionalization and drug development.
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