Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents

Area of Science:

• Chemical Biology
• Organic Chemistry
• Nucleic Acid Chemistry

Background:

• Organometallic reagents are vital for bioconjugation, with advancements enabling peptide and protein coupling in aqueous solutions.
• Existing methods lack organometallic approaches for conjugating oligonucleotides to other biomolecules.

Purpose of the Study:

• To introduce novel bifunctional palladium(II)-oxidative addition complexes (OACs) for oligonucleotide bioconjugation.
• To establish a robust method for creating stable oligonucleotide-palladium conjugates.

Main Methods:

• Synthesis of bifunctional palladium(II)-oxidative addition complexes (OACs).
• Chemoselective reaction of OACs with amine-modified oligonucleotides.
• Site-selective C-S arylation of oligonucleotide-palladium complexes with thiol-containing biomolecules.

Main Results:

• First isolable and bench-stable oligonucleotide-palladium(II) OACs were generated.
• High-yielding (>80%) conjugation of oligonucleotides to peptides, proteins, small molecules, and other oligonucleotides was achieved.
• Multiple oligonucleotides were successfully conjugated onto a monoclonal antibody.

Conclusions:

• Bifunctional palladium(II)-OACs provide a versatile and efficient platform for oligonucleotide bioconjugation.
• This method overcomes limitations in current organometallic strategies for oligonucleotide modification.
• The developed approach enables the synthesis of complex biomolecular conjugates for diverse applications.