A Versatile Disulfide-Containing Solid-Support Strategy for 3'-Modifiers in Oligonucleotides: Introducing Modular
Jagandeep S Saraya1, Nicholas G Horton1, Michael J Capperauld1
1Department of Chemistry, University of Guelph, 50 Stone Rd E, Guelph, Ontario, N1G 2W1, Canada.
Chemistry, an Asian Journal
|June 2, 2025
Summary
This study introduces a novel disulfide-containing linker for cost-effective oligonucleotide synthesis, enabling 3'-amino and 3'-phosphate modifications. This advance simplifies workflows and expands applications in bioconjugation and origins of life research.
Area of Science:
- Chemical Biology
- Synthetic Chemistry
- Molecular Biology
Background:
- Chemical modifications enhance oligonucleotide functionality for various applications.
- Amino-modifiers are crucial for bioconjugation and immobilization.
- Current methods for modified nucleic acid synthesis can be complex and inefficient.
Purpose of the Study:
- To develop a cost-effective, disulfide-containing solid-support linker for oligonucleotide synthesis.
- To enable on-column synthesis of nucleic acids with 3 ahydro-amino or 3 ahydro-phosphate modifications.
- To introduce a versatile modular tandem oligonucleotide synthesis (mTOS) approach.
Main Methods:
- Development of a disulfide-containing solid-support linkage.
- On-column synthesis of DNA and RNA with 3 ahydro-amino-2 ahydro,3 ahydro-dideoxyribosides.
- Implementation of an on-column deprotection protocol.
- Introduction of the modular tandem oligonucleotide synthesis (mTOS) method.
Main Results:
- Successful on-column synthesis of nucleic acids with 3 ahydro-amino and 3 ahydro-phosphate modifications.
- Enabled synthesis of DNA/RNA with 3 ahydro-amino-2 ahydro,3 ahydro-dideoxyribosides from unprotected mononucleosides.
- Eliminated precipitation step in RNA workflows, improving recovery.
- Demonstrated selective release of downstream strands using mTOS.
Conclusions:
- The novel linker and mTOS approach offer a cost-effective and efficient method for synthesizing modified oligonucleotides.
- These advances facilitate bioconjugation, biotechnology, and studies on prebiotic replication.
- Broadened utility of chemically modified nucleic acids in diverse research areas.
